small molecules

2026-08-10 | Methods and Compositions for Treatment and Patient Stratification of Vascular Disease by Restoration of an Endothelial-Protective Program and Reversal of Endothelial-to-Mesenchymal Transition (Provisional Patent Specification)

Specification of U.S. Provisional Patent Application No. 64/130,015 (filed August 10, 2026; inventor Glen Charles Ritschel, Ritschel Research), archived as a citable, timestamped defensive-publication disclosure. This disclosure describes a single-cell RNA-sequencing-derived signature of a pathogenic endothelium that has lost a bone-morphogenetic-protein- and KLF2/KLF4-driven protective program and has undergone endothelial-to-mesenchymal transition (EndoMT), and a method of treating, stratifying, and restoring that cell state across a genus of vascular diseases. The two-sided EndoMT-EC signature comprises an endothelial-identity and BMP-protective down-program to be restored (PECAM1, CDH5, KLF2, KLF4, TEK, BMPR2, ID1, and related genes) and a mesenchymal and matrix up-program to be suppressed (ACTA2, TAGLN, SERPINE1, fibrillar collagens, and related genes). The state is validated in systemic sclerosis pulmonary arterial hypertension endothelium, where it is disease-distinct from idiopathic PAH with independent peer-reviewed corroboration (Tuhy et al., senior author Simpson, Circ Genom Precis Med 2025); is shared in systemic sclerosis digital vasculopathy; and is human-genetically anchored in hereditary hemorrhagic telangiectasia, a disease caused by loss-of-function mutations in ALK1 and endoglin at the top of the same BMP axis. The disclosure provides the signature and an orthogonal endothelial-protective-loss score; a method of measuring the state; a method of selecting agents that restore the protective program and reverse EndoMT (KLF2/KLF4-inducing statins and AMPK activators, ROCK2 inhibitors such as belumosudil, PPAR-gamma agonists such as pioglitazone, and BMP-receptor-pathway activators), optionally in combination with fibroblast-directed or macrophage-directed antifibrotic agents targeting the other effectors of the same disease; and a stratification biomarker defining a responder subgroup. The genus is limited to vascular diseases where loss of the program is validated or genetically established. Discovery-stage computational work; the disease-associated cell state is validated in independent human data and human genetics, while reversal by the named agents is mechanism-anchored, with a defined in-vitro pulmonary-endothelial reversal assay, and is not yet demonstrated clinically. Not medical or legal advice.

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2026-08-10 | A Shared Endothelial-Protective Program Lost Across Systemic Sclerosis Pulmonary Arterial Hypertension, Digital Vasculopathy, and Hereditary Hemorrhagic Telangiectasia: An EndoMT Cell-State Signature and an Endothelial-Restoration Strategy

The vascular endothelium maintains its own quiescence through a protective program built on BMP signaling (ALK1, endoglin, BMPR2) and the flow-responsive factors KLF2 and KLF4. This working paper defines a two-sided, single-cell-RNA-seq-derived endothelial cell-state signature of the loss of that program and of endothelial-to-mesenchymal transition (EndoMT): a DOWN set of endothelial-identity and BMP-protective genes that falls, and an UP set of mesenchymal and matrix genes that rises, in the pathogenic endothelium. Loss of the program is shown to be shared across three separately analyzed vascular diseases: systemic sclerosis pulmonary arterial hypertension (SSc-PAH), where the EndoMT state is elevated and molecularly distinct from idiopathic PAH, with independent peer-reviewed single-cell corroboration; systemic sclerosis digital vasculopathy, where the protective-loss program is elevated across cohorts; and hereditary hemorrhagic telangiectasia (HHT), where ALK1 and endoglin loss-of-function mutations at the top of the axis establish that loss of the program is causal, not correlative. One endothelial-restoration strategy and a shared stratification biomarker are proposed for the genus, with mechanism-anchored restoring agents (KLF2/KLF4-inducing statins and AMPK activators, ROCK2 inhibitors, PPAR-gamma agonists, and BMP-receptor-pathway activators). The boundaries of the convergence are documented honestly, including a related arm (dermatomyositis) whose injury-marker pole did not replicate and which is excluded from the genus. This is a discovery-stage computational study intended to prioritize candidates for experimental validation. The associated provisional specification is archived at DOI 10.5281/zenodo.21875485; U.S. Provisional Patent Application No. 64/130,015 was filed August 10, 2026.

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2026-07-28 | Evidence for PDZ-Binding Kinase in Lung Disease With an Emphasis on PAH.

Originally named T-cell-originated Lymphokine-activated killer protein kinase (TOPK), PDZ-Binding Kinase (PBK) is a serine/threonine kinase that is a member of the family of mitogen-activated protein kinases (MAPKKs), which is overexpressed in lung cancer and interstitial pulmonary fibrosis (IPF). Along these lines, recent work also shows that PBK expression is upregulated in pulmonary arterial hypertension (PAH) in part due to the inappropriate proliferation of pulmonary arterial smooth muscle cells (PASMC), similar to the hyper-proliferative cellular properties seen in both lung cancer and IPF. Genetic knock-out of PBK as well as pharmacologically selective inhibitors of PBK improve PA remodeling and cardiopulmonary function. Further, PBK bound to the Protein Regulator of Cytokinesis 1 (PRC1) induces PRC1 phosphorylation and cytokinesis in PASMC, and thus, it is conjectured that PBK enhances PASMC proliferation via PRC1-mediated cytokinesis, identifying a key mechanism which contributes to the pathologic pulmonary vascular remodeling that occurs in PAH. Towards this end, along with the already published studies showing that PBK is involved in both lung cancer and IPF, PBK-mediated pulmonary vascular remodeling reveals a new signaling pathway in lung vascular disease and a novel mechanism of PASMC proliferation. Exploration of this signaling pathway will advance the utility of identifying novel therapeutic approaches targeting PBK-mediated cytokinesis to reduce pulmonary vascular remodeling (as seen in PAH) and subsequently improve the morbidity and mortality associated with lung vascular disease. Collectively, the literature strongly suggests that PBK is a worthy and viable therapeutic target to pursue in the context of lung disease.

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2026-07-26 | Misdiagnosed as Idiopathic PAH: Methylmalonic Acidemia as a Reversible Cause of Pediatric Pulmonary Hypertension.

Methylmalonic acidemia (MMA)-induced pulmonary hypertension (PH) is a rare but treatable cause of pediatric PH, often misdiagnosed as idiopathic pulmonary arterial hypertension (IPAH). We conducted a 10-year, multicenter retrospective study of children with clinically unexplained PH. Thirteen patients with MMA-PH were compared to 113 with idiopathic or hereditary PAH (IPAH/HPAH) regarding clinical features, hemodynamics, and outcomes. MMA-PH accounted for 2.7% of pediatric PH cases. Patients presented younger (7±4 vs. 11±5 years, p=0.008) and exhibited higher rates of growth failure (84.6% vs. 15.9%, p<0.001), anorexia/malnutrition (76.9% vs. 14.2%, p<0.001), recurrent pneumonia (46.2% vs. 13.3%, p=0.003), microscopic hematuria (84.6% vs. 1.8%, p<0.001), and proteinuria (31% vs. 4.4%, p=0.007) than IPAH/HPAH. All had the combined MMA subtype with markedly elevated homocysteine (median 87 µmol/L vs. 18 µmol/L, p<0.001). With metabolic therapy (hydroxocobalamin, betaine, etc.) and short-term pulmonary vasodilators, all achieved complete clinical and hemodynamic remission within one year. Median follow-up was 7.0 years; no relapse occurred. Elevated total homocysteine and multisystem involvement should prompt metabolic screening in children with unexplained PH. Early diagnosis and metabolite-targeted treatment can lead to sustained, nearly-curative outcomes, distinguishing MMA-PH from IPAH/HPAH. Routine homocysteine testing is recommended in the diagnostic workup of pediatric PH.

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2026-07-25 | Empagliflozin Ameliorates Experimental Pulmonary Vascular Remodeling, but May Not Benefit Patients With Pulmonary Arterial Hypertension.

Sodium glucose cotransporter 2 inhibitors may improve mitochondrial biogenesis and attenuate pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). We investigated the impact of empagliflozin in PAH. Microvascular endothelial cells (MVECs) were collected from the lungs of control patients and patients with PAH, and the effects of empagliflozin on MVECs were evaluated. Subsequently, treatment effects of empagliflozin (300 mg/kg chow, n=12) or placebo (n=12) were evaluated in experimental PAH rats (SU5416 injection followed by 3 weeks of hypoxia). In addition, we conducted a phase IIa proof-of-concept trial, EMPHOWER PoC (Feasibility Study of Empagliflozin as Treatment for Idiopathic Pulmonary Arterial Hypertension), to assess the feasibility of 12 weeks of empagliflozin treatment in patients with PAH. In comparison to control MVECs, PAH MVECs showed increased protein expression of sodium glucose cotransporter 2. Empagliflozin enhanced expression of mitochondrial-encoded genes and respiration, while attenuating oxidative stress and proliferation of PAH MVECs. In SU5416 and hypoxia rats, chronic empagliflozin treatment reduced pulmonary vascular resistance and thickening of the intima of small pulmonary arteries. Finally, 8 patients diagnosed with idiopathic and heritable PAH were enrolled in EMPHOWER PoC. No discontinuation of empagliflozin during the study period or treatment-associated serious adverse events were observed. There were no changes in N-terminal pro-B-type natriuretic peptide, World Health Organization functional class, 6-minute walk distance, or emPHasis score; however, right ventricular ejection fraction slightly worsened (from 45%±10% to 38%±12%, P=0.031). Empagliflozin attenuates proliferation of PAH MVECs. Empagliflozin reduces pulmonary vascular remodeling in experimental PAH. While 12 weeks of empagliflozin treatment was feasible in patients with idiopathic or hereditary PAH, we observed signs of right ventricular deterioration. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05493371.

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proteins

2026-07-09 | GDF11 regulates hypoxia-induced pulmonary endothelial cell pyroptosis through SOX2/NLRP3 axis.

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, which is driven in part by endothelial dysfunction. Growth differentiation factor 11 (GDF11) has emerged as an important regulator of vascular homeostasis; however, its role in pulmonary artery endothelial cell (PAEC) pyroptosis remains unclear. This study aimed to define the contribution of GDF11 to hypoxia-induced PAH and its mechanistic association with inflammasome activation. Endothelial-specific Gdf11 knockout mice were exposed to chronic hypoxia to evaluate hemodynamics, right ventricular hypertrophy, pulmonary vascular remodeling, and endothelial pyroptosis. In vitro, PAECs were subjected to GDF11 knockdown or adenoviral-mediated overexpression. Pyroptosis and downstream signaling were assessed by Western blotting, Annexin V/propidium iodide staining, lactate dehydrogenase release assay, Hoechst/propidium iodide imaging, immunofluorescence, and chromatin immunoprecipitation. GDF11 expression was increased in hypoxic lung tissues and PAECs. Endothelial-specific deletion of Gdf11 significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling, and suppressed hypoxia-induced PAEC pyroptosis. In vitro, GDF11 knockdown attenuated hypoxia-induced pyroptosis, whereas GDF11 overexpression exacerbated this response. Mechanistically, SOX2 was identified as a downstream transcriptional effector of GDF11 and was found to directly bind to the Nlrp3 promoter, thereby promoting inflammasome activation and pyroptosis. These findings identify a previously unrecognized GDF11-SOX2-NLRP3 axis that promotes pulmonary endothelial pyroptosis and accelerates PAH progression. Targeting this pathway may provide new opportunities for biomarker development and therapeutic intervention in PAH.

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2026-06-18 | Pulmonary arterial hypertension from a translational perspective: Bridging pathophysiology and treatment.

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder defined by elevated pulmonary arterial pressure and vascular resistance, ultimately leading to right ventricular failure and premature death. Once considered a disease of pure vasoconstriction, PAH is now recognized as a complex vasculopathy involving endothelial dysfunction, inflammation, metabolic dysregulation, and genetic susceptibility. The pulmonary vasculature is dynamically narrowed by vasoconstriction, structurally obstructed by smooth muscle and endothelial proliferation, and pathologically stiffened by fibrosis and extracellular matrix deposition. Multiple cell types including endothelial cells, smooth muscle cells, fibroblasts, and immune cells contribute to this remodeling process. At the molecular level, hyperproliferative, apoptosis-resistant phenotypes emerge through mitochondrial dysfunction, oxidative stress, and endothelial-to-mesenchymal transition, which together drive a Warburg-like metabolic shift favoring glycolysis over oxidative phosphorylation. Chronic immune activation, characterized by cytokine release, T-cell and macrophage infiltration, and disrupted immune regulation, further amplifies vascular injury. Genetic studies have identified mutations in BMPR2, TBX4, SOX17 , and other regulators of the bone morphogenic protein (BMP)/transform-ing growth factor-β (TGF-β) pathway as key contributors to heritable and idiopathic forms of PAH, highlighting impaired endothelial repair and aberrant signaling as central mechanisms. Recent translational breakthroughs have yielded novel therapeutic strategies beyond traditional vasodilators. Agents targeting the BMP/TGF-β axis (e.g., sotatercept), growth factor signaling (seralutinib), inflammatory pathways (tocilizumab, rituximab), and metabolic remodeling (pyruvate dehydrogenase kinases [PDK] and fatty acid oxidation [FAO] modulators) are redefining treatment paradigms. Concurrently, large-scale multi-omics initiatives such as PVDOMICS and PHOENIKS enable deep phenotyping, which unravels molecular endotypes and informs precision medicine approaches. This review summarizes the pathophysiology of PAH and the ongoing clinical trials in the PAH field.

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2026-05-18 | Sotatercept in TBX4 Associated Heritable Pulmonary Arterial Hypertension: A Case Report of a Super Responder.

Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary arteries. Progressively increasing pulmonary artery pressure may lead to fatal failure of the right ventricle, necessitating aggressive drug treatment. Sotatercept, a novel drug for PAH-targeted therapy, shows promising results in clinical trials. Nevertheless, efficacy in the heterogeneous PAH population and long-term outcomes have yet to be investigated. This case report illustrates the life-changing effects of sotatercept in a patient with heritable PAH associated with a TBX4 mutation. Our patient faced near immobility, oxygen dependency, and was listed for lung transplantation in November 2023. Following sotatercept administration from July 2024 onward, she started sporting activities and has been removed from the transplantation waiting list. Thereby, this case illustrates an exceptional response to sotatercept in a patient with TBX4-associated heritable PAH. Positive effects persist 1 year after initiation without significant side effects.

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2026-05-01 | B106-21 Safety and Efficacy of Sotatercept in Pulmonary Arterial Hypertension Patients With Comorbidities

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive disease characterized by functional deterioration and high mortality. Previous studies have demonstrated that the presence of comorbidities affects tolerability of PH therapies and have a subsequent blunted response. This study assessed the efficacy and tolerability of Sotatercept in patients with PAH and multiple comorbidities. Methods Of 130 patients initiated on Sotatercept, 23 patients had two available sets of hemodynamic data; one prior to Sotatercept initation and at least one follow-up right heart catheterization (RHC). Real word data from these 23 PAH patients were reviewed. We assessed hemodynamics parameters such as echo changes, PVR, and mPAP. Functional, hemodynamic and laboratory parameters were assessed at baseline and at least 6 months after therapy. Results Mean age was 52 ± 14 years, 83% female, 65% IPAH, 22% CTD, 4% Familial PAH and 9% were Drug-induced. Comorbidities included obesity (52%) with a median BMI of 31.1± 3.0 kg/m2, OSA (52%), Hypertension (43%), CKD (30%), and diabetes (22%). 13% (n = 3) of patients had 0 comorbidities, 30% (n = 7) of patients had 1 comorbidity, 30% (n = 7) of patients had 2 comorbidities, 4 % (n = 1) of patients had 3 comorbidities, 13% (n = 3) of patients had 4 comorbidities, and 9% (n = 2) of patients had 5 comorbidities. 83% of patients were on triple therapy prior to Sotatercept and remained on stable background therapy after initiation. Despite the presence of comorbidities, Sotatercept treatment led to significant improvements in 6-minute walk distance (327 to 377m, p = 0.011), mean pulmonary arterial pressure (47 to 36 mmHg, p &lt; 0.001), PVR (7.7 to 5.1 WU, p = 0.011), and hemoglobin increase from 12.20 ± 1.88 to 13.67 ± 2.36 g/dL (p &lt; 0.001) after median of 14 doses of Sotatercept over a median period of 14 months. NT-proBNP levels were evaluated from baseline to the most recent follow-up, showing reduction from 541.00 (97.00,2323.00) to 194.00 (57, 427) pg/mL (p = 0.006). Functional class improved in 26% of patients with a median REVEAL Lite 2 score of 8 at baseline to 6 at the most recent assessment, p = &lt;0.001. There was no increase in bleeding events or PH-related hospitalizations after treatment. There was no discontinuation of Sotatercept due to comorbidity related tolerability issues. Conclusions Our findings indicate that Sotatercept was well tolerated and associated with significant hemodynamic and functional improvement in patients with PAH with associated comorbidities. These findings support the clinical benefit of Sotatercept across diverse, real-world PAH populations. This abstract is funded by: None

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2026-05-01 | C26-16 Differential Tgfβ Antagonism in a Mouse Model of Peripheral Arteriovenous Malformation

Abstract Rationale ACTRIIA-Fc (sotatercept), the first-in-class Activin Signaling Inhibitor (ASI) therapy, has provided a new therapeutic option for pulmonary arterial hypertension (PAH) based on modulation of bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ) signaling. Heritable PAH is associated with Loss-of-Function (LOF) mutations in several receptors and ligands of this pathway, including GDF2, BMP10, BMPR2, ACVRL1, ENG, and SMAD4, several of which are also associated with hereditary hemorrhagic telangiectasia (HHT) syndrome. Several drug candidates in this class have demonstrated the potential to induce arteriovenous malformations (AVMs), manifesting as epistaxis, telangiectasia, gastrointestinal AVMs, and pulmonary AVMs. We have devised a sensitive pre-clinical model to screen BMP/TGFβ modulating compounds for the potential to induce AVM in a genetically susceptible mouse strain. Methods We tested several recombinant ligand traps or antibodies that have been explored as candidate drugs in experimental PH or clinical PAH: anti-BMP9, anti-BMP10, ALK1-Fc (a BMP9/BMP10 ligand trap), ACTRIIA-Fc a.k.a. sotatercept, ACTRIIB-Fc (a combined activin/GDF/BMP9/BMP10 ligand trap), and isotype control. These antagonists were characterized for their binding affinities to an array of BMP/TGFβ ligands (BMP9, BMP10, BMP2, BMP6, GDF7, GDF8, activin A, activin B, and TGFβ1) using Bio-Layer Interferometry. Juvenile 129X1/SvJ mice were treated with recombinant BMP/activin ligand-traps or neutralizing antibodies (5-10 mg/kg i.p. twice weekly) for fifteen weeks, with serial monitoring of telangiectasias or bleeding via digital capillaroscopy, and complete blood counts at the completion of the study. Results ACTRIIA-Fc/sotatercept potently inhibited activin A/B, GDF8/11, and BMP10, but also had moderate affinity for BMP9. Treatment with ACTRIIB-Fc or ALK1-Fc led to high frequency (&gt;50%) digital AVM formation and bleeding in hind limb digits within 6 weeks, with greater penetrance occurring when treatment was started at a younger age. Treatment with ACTRIIA-Fc, anti-BMP10, or anti-BMP9 led to less frequent and milder AVMs, and at a delayed interval as compared to ACTRIIB-Fc or ALK1-Fc, whereas treatment with a combination of anti-BMP9 and anti-BMP10 elicited effects which were comparable to ACTRIIB-Fc or ALK1-Fc. Conclusions HHT mimicry in a susceptible mouse strain is age dependent. Potent antagonism of BMP9/BMP10 via ACTRIIB-Fc, ALK1-Fc, or a combination of anti-BMP9 and anti-BMP10 elicited potent AVM formation and bleeding in an HHT-prone mouse strain, whereas multi-ligand trap ACTRIIA-Fc elicited milder effects. This assay may be useful for screening the potential risk of AVMs in candidate BMP/TGFβ targeted therapies for PAH. This abstract is funded by: NIH

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oligonucleotides

2026-02-17 | GLI1 Promotes Hypoxia Induced Pyroptosis of PASMCs and Aggravates Pulmonary Arterial Hypertension in Rats by Upregulating HDAC1 Expression.

Existing research data show that pulmonary artery smooth muscle cells (PASMCs) can play a very important role in the occurrence and development of pulmonary hypertension (PAH). Through in-depth study and analysis, we found that glioma-associated oncogene family zinc finger 1 (GLI1) has a significantly higher expression level in the nucleus and cytoplasm of hypoxic PASMCs. Next, GLI1 overexpression plasmid or small interfering RNA were transfected into hypoxic PASMCs respectively, and GLI1 promoted the migration and pyroptosis of hypoxic PASMCs, while GLI1 silencing had the opposite effect. Next, histone deacetylase 1 (HDAC1) was verified to be a binding protein of GLI1, and GLI1 promotes HDAC1 protein expression. Then, HDAC1 promoted abnormal of hypoxic PASMCs, while HDAC1 knockdown inhibited cell migration and pyroptosis. Then, the hypoxic PASMCs were transfected si-GLI1 alone or together with HDAC1-OE, and further confirm that GLI1 promotes hypoxia induced pyroptosis and abnormal proliferation of PASMCs by upregulating HDAC1 protein expression. In addition, we constructed a PAH rat model, and found that GLI1 silenced PAH rats had reduced expression of markers related to pyroptosis and smooth muscle cell proliferation in the lung tissue, and the lung injury of rats was reduced, and the lung function was significantly improved, suggesting that GLI1 silencing is beneficial to PAH in rats.

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2025-06-26 | LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension.

In this study, we define the mechanistic association between long noncoding RNA: ENST00000495536 (lnc-536) and transcription factor HOXB13 (homeobox B13) in mediating proproliferative smooth muscle phenotype associated with pulmonary hypertension. In vitro knockdown or knockin, along with RNA pull-down and immunoprecipitation studies, were used to evaluate the role of lnc-536 and HOXB13 in regulating pulmonary arterial smooth muscle cell (PASMCs) phenotype. The in vivo role was determined by injecting lnc-536 antisense oligos in pulmonary hypertensive rats. Increased levels of lnc-536 promote the proliferative phenotype of PASMCs by downregulating the expression of the tumor suppressor: HOXB13. Knockdown of lnc-536 and overexpression of HOXB13 in proliferative PASMCs resulted in increased expression of VGLL4 (vestigial-like family member 4), a negative regulator of Hippo and Wnt (Wingless-related integration site) signaling pathways, with a corresponding decrease in TEAD4 (TEA domain family member 1) expression. The lnc-536 pull-down assay and RNA-immunoprecipitation demonstrated the interactions of lnc-536 with RBP (RNA-binding protein): RBM25 (RNA-binding motif 25) and direct interactions of RBM25 with SFPQ (splicing factor proline/glutamine-rich), a transcriptional regulator that has a binding motif on HOXB13. The knockdown of RBM25 in the hyperproliferative PASMCs resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Furthermore, the increased levels of lnc-536 and decreased levels of HOXB13 were observed in PASMCs from idiopathic pulmonary hypertension patients but not in cells from familial pulmonary hypertension patients. We confirmed that lnc-536 contributes to the RBM25-mediated remodeling of the SFPQ-HOXB13 complex in the idiopathic PAH-PASMCs as well. Finally, in vivo inhibition of lnc-536 using GapmeRs (Gapmer antisense oligonucleotides) in Sugen-hypoxia and HIV-transgenic pulmonary hypertension rats prevented the increase in right ventricular systolic pressure, right ventricular hypertrophy/fibrosis, and pulmonary vascular remodeling with a parallel increase in HOXB13 expression in rat PASMCs. Lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to a decrease in HOXB13 expression and hyperproliferation of smooth muscle cells by potentially regulating Wnt and Hippo signaling associated with PAH development.

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2025-05-19 | ca-circSCN8A Promotes HPASMCs Ferroptosis via LLPS Initiated R-Loop.

Ferroptosis has been implicated in pulmonary hypertension (PH), and chromatin-associated RNAs are increasingly recognized as key regulators of this process. However, the detailed mechanism remains unexplored. Bioinformatics, Sanger sequencing, and RNase R digestion were used to identify the upregulation of ca-circSCN8A. Functional gain and loss assays were used to unveil the role of ca-circSCN8A in hypoxic redox-dependent ferroptosis in human pulmonary arterial smooth muscle cells and a PH mice model. Interaction between ca-circSCN8A and FUS was detected via RNA immunoprecipitation and pull-down assays. Fluorescence recovery after photobleaching, ChIRP-qPCR (Chromatin Isolation by RNA Purification followed by Quatitative PCR), malondialdehyde, reduced glutathione, and glutathione were conducted to explore the potential molecular mechanism. ca-circSCN8A was identified and confirmed to be upregulated in PH. Its overexpression promoted hypoxia-induced ferroptosis in human pulmonary arterial smooth muscle cells. Under hypoxic conditions, ca-circSCN8A recruited EP300 to facilitate the lactylation of FUS (Fused in Sarcoma), triggering the formation of a ca-circSCN8A/FUS/EP300 complex via liquid-liquid phase separation. Liquid-liquid phase separation maintained the stability of the R-loop formed by ca-circSCN8A and ferroptosis-related gene SLC7A11 (solute carrier family 7 member 11) promoter that inhibits its transcription, further result in the disruption of the redox homeostasis and causing ferroptosis in human pulmonary arterial smooth muscle cells. ca-circSCN8A recruits EP300 to promote the lactylation of FUS, thereby driving liquid-liquid phase separation-mediated complex formation with FUS and EP300. This process enables ca-circSCN8A to form an R-loop with the nonhost SLC7A11 promoter, contributing to the regulation of hypoxia-induced ferroptosis in human pulmonary arterial smooth muscle cells. This study provides the first evidence that circRNAs can form R-loops with nonhost genes in a liquid-liquid phase separation-dependent manner. Our findings highlight ca-circSCN8A as a crucial regulator of ferroptosis in hypoxic PH and a potential therapeutic target for PH.

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2024-06-15 | Otud6b induces pulmonary arterial hypertension by mediating the Calpain-1/HIF-1α signaling pathway.

Pulmonary hypertension (PAH) is a cardiopulmonary disease in which pulmonary artery pressure continues to rise, leading to right heart failure and death. Otud6b is a member of the ubiquitin family and is involved in cell proliferation, apoptosis and inflammation. The aim of this study was to understand the role and mechanism of Otud6b in PAH. C57BL/6 and Calpain-1 knockout (KO) mice were exposed to a PAH model induced by 10% oxygen. Human pulmonary artery endothelial cells (HPACEs) and human pulmonary artery smooth muscle cells (HPASMCs) were exposed to 3% oxygen to establish an in vitro model. Proteomics was used to determine the role of Otud6b and its relationship to Calpain-1/HIF-1α signaling. The increased expression of Otud6b is associated with the progression of PAH. ROtud6b activates Otud6b, induces HIF-1α activation, increases the production of ET-1 and VEGF, and further aggravates endothelial injury. Reducing Otud6b expression by tracheal infusion of siOtud6b has the opposite effect, improving hemodynamic and cardiac response to PAH, reducing the release of Calpain-1 and HIF-1α, and eliminating the pro-inflammatory and apoptotic effects of Otud6b. At the same time, we also found that blocking Calpain-1 reduced the effect of Otud6b on HIF-1α, and inhibiting HIF-1α reduced the expression of Calpain-1 and Otud6b. Our study shows that increased Otud6b expression during hypoxia promotes the development of PAH models through a positive feedback loop between HIF-1α and Calpain-1. Therefore, we use Otud6b as a biomarker of PAH severity, and regulating Otud6b expression may be an effective target for the treatment of PAH.

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2023-12-22 | Circ_0068481 Affects the Human Pulmonary Artery Smooth Muscle Cells' Progression by miR-361-3p/KLF5 Axis.

Uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). In this work, we defined the precise part of circ_0068481 in PASMC proliferation and migration induced by hypoxia. We hypothesized that circ_0068481 enhanced hypoxia-induced PASMC proliferation, invasion, and migration through the microRNA (miR)-361-3p/Krüppel-like factor 5 (KLF5) pathway. Human PASMCs (hPASMCs) were exposed to hypoxic (3% O2) conditions. Circ_0068481, miR-361-3p, and KLF5 levels were gauged by qRT-PCR and western blot. Cell viability, proliferation, invasion, and migration were detected by XTT, EdU incorporation, transwell, and wound-healing assays, respectively. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were performed to confirm the direct relationship between miR-361-3p and circ_0068481 or KLF5. Circ_0068481 expression was increased in the serum of PAH patients and hypoxia-induced hPASMCs. Downregulation of circ_0068481 attenuated hypoxia-induced promotion in hPASMC proliferation, invasion, and migration. Circ_0068481 directly targeted miR-361-3p, and miR-361-3p downregulation reversed the inhibitory effects of circ_0068481 silencing on hypoxia-induced hPASMC proliferation, invasion, and migration. KLF5 was a direct miR-361-3p target, and miR-361-3p upregulation mitigated hypoxia-induced hPASMC proliferation, invasion, and migration by inhibiting KLF5 expression. Moreover, circ_0068481-induced KLF5 expression by binding to miR-361-3p in hypoxic hPASMCs. Circ_0068481 knockdown ameliorated hypoxia-induced hPASMC proliferation, invasion, and migration at least in part through the miR-361-3p/KLF5 axis.

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antibodies

2026-08-12 | Clinical characteristics of pulmonary hypertension associated with hereditary hemorrhagic telangiectasia treated with bevacizumab: a single-center case series.

Pulmonary hypertension (PH) is a severe complication of hereditary hemorrhagic telangiectasia (HHT). The experience with bevacizumab in HHT-PH is limited. Therefore, the aim was to provide our single-center experience with the use of bevacizumab in patients with HHT-PH. The clinical data of HHT-PH patients treated with bevacizumab were retrospectively reviewed between September 2021 and June 2024 at Beijing Anzhen Hospital, Capital Medical University. To describe the clinical features of these patients, we recruited pulmonary arterial hypertension (PAH) patients and PH associated with left heart diseases (PH-LHD) patients, matched for age and gender. The symptoms, underlying diseases, medication history, laboratory test results, treatments, and therapeutic responses were investigated retrospectively in all patients. In total, six cases of HHT-PH that were treated with bevacizumab, of which only five received follow-up after completing the 3-month induction therapy. Compared with PAH and PH-LHD patients, HHT-PH patients were characterized by high cardiac index (CI) [HHT-PH vs. PAH vs. PH-LHD: 6.10 (3.77, 7.60) vs. 2.37 (1.92, 3.03) vs. 2.38 (1.91, 2.63) L/min/m2, P=0.001] in conjunction with low systemic vascular resistance [740.93±333.06 vs. 1,836.07±673.64 vs. 1,667.78±453.84 dyn·s·cm-5, P=0.001] and PVR [189.94 (54.46, 289.89) vs. 886.70 (705.18, 1278.68) vs. 229.48 (179.15, 416.60) dyn·s·cm-5, P=0.002]. All the HHT-PH patients experienced significant improvements in symptoms (World Health Organization functional class), hemoglobin, brain natriuretic peptide levels and tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure after the induction therapy with bevacizumab. Of note, two of the five patients had a baseline CI <4 L/min/m2, yet still experienced clinically meaningful improvement after the bevacizumab induction therapy. Four out of five patients experienced improvements in hemodynamics and 6-minute walking distance after the induction therapy. Our study found that the hemodynamic profile of HHT-PH patients treated with bevacizumab differed significantly from that of PAH and PH-LHD. There might be patients with a CI below 4 L/min/m2 who were still in a high-output state and could benefit from bevacizumab treatment in clinical practice.

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2026-02-18 | GM-CSF exacerbates pulmonary arterial hypertension via CCL2/CCR2-axis-mediated macrophage NLRP3 inflammasome activation.

Pulmonary arterial hypertension (PAH) is a fatal disease marked by pulmonary vascular remodeling. Although endothelial dysfunction and immune cell infiltration are central to its pathogenesis, the specific signaling mechanisms linking these elements remain unclear. This study investigates a novel pathway whereby endothelial cell-derived GM-CSF drives macrophage-dependent inflammation via the CCL2/CCR2 axis, ultimately promoting PAH progression through NLRP3 inflammasome activation. PAH mouse model was established using a high-fat diet (HFD) combined with L-NAME. Comprehensive in vivo assessments included echocardiography to evaluate cardiac function, Masson's Trichrome to measure vascular remodeling. In vitro, a co-culture system of mouse pulmonary arterial endothelial cells (MPAECs) and bone marrow-derived macrophages (BMDMs) was used, with palmitic acid (PA) stimulation to mimic PAH conditions. Key interventions involved administering a GM-CSF neutralizing antibody, depleting macrophages with clodronate liposomes, and utilizing Ccr2-/- mice. PAH mice exhibited significant pulmonary arterial wall thickening, right heart dysfunction, and increased lung wet-to-dry weight ratio. This was accompanied by early and sustained upregulation of GM-CSF and CCL2 in lung tissues, extensive infiltration of CCR2+ macrophages, and activation of the NLRP3 inflammasome cascade. In vitro, PA-stimulated MPAECs released GM-CSF, which promoted macrophage migration and CCL2 secretion, induced a pro-inflammatory M1 phenotype, and activated the NLRP3 pathway. Crucially, in vivo therapeutic interventions demonstrated that neutralizing GM-CSF, depleting macrophages, or knocking out Ccr2 all significantly alleviated PAH pathology. This study confirms that endothelial cell-derived GM-CSF promotes macrophage-NLRP3 inflammasome via the CCL2/CCR2 axis, thereby driving the progression of PAH. This axis may represent a promising therapeutic target for PAH.

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2026-01-05 | Clinical Applications of Ligand Traps Targeting Activin Type II Receptors.

This review summarizes recent advances in ligand trap therapies targeting activin type II receptors [ActRIIA/ACVR2A and ActRIIB/ACVR2B], which serve as shared receptors for members of the TGF-β family, including activins, GDF11, and myostatin [MSTN]. These receptors mediate Smad2/3 signaling and play critical roles in hematopoiesis, vascular homeostasis, and muscle regulation. Two peptide-based ligand traps have recently received clinical approval: luspatercept [ActRIIB-Fc], an erythroid maturation agent, and sotatercept [ActRIIA-Fc], a novel therapeutic agent for pulmonary arterial hypertension [PAH]. Luspatercept primarily inhibits activin B and GDF11, thereby promoting late-stage erythropoiesis and demonstrating efficacy in anemia associated with conditions such as myelodysplastic syndromes [MDS] and β-thalassemia. Sotatercept binds activins and GDFs to rebalance Smad2/3 and Smad1/5/8 signaling, thereby improving vascular remodeling in PAH. Although both agents have failed to increase skeletal muscle mass in clinical trials consistently, they represent significant advances in the treatment of hematopoietic and vascular disorders. Future studies should focus on optimal dosing strategies, long-term safety, and potential synergistic effects when combined with other therapeutic modalities.

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2025-12-02 | Endoglin as a BMP9 Co-Receptor in Vascular Endothelial Cells: Prodomain Displacement and TGFBRII Recruitment

Endoglin (ENG) is a single-pass transmembrane protein highly expressed in vascular endothelial cells (ECs), where it plays fundamental roles in EC functions. ENG is implicated in several cardiovascular disorders including hereditary haemorrhagic telangiectasia, pulmonary arterial hypertension (PAH) and preeclampsia. However, molecular mechanisms underlying ENG function are not fully understood. Initially identified as a co-receptor for TGF-β signalling, ENG’s extracellular domain was later found to only bind BMP9 and BMP10 with high affinity. The relationship between these two observations is unclear. Here, we provide evidence for two primary functions of co-receptor ENG. First, ENG efficiently displaces prodomains from BMP9 and BMP10, enabling effective capturing of both ligands from the circulation. Second, ENG binds to and recruits TGFBRII into the BMP9 signalling complex, thereby explaining ENG’s involvement in both TGF-β and BMP9 pathways. We identify BMP9 target genes NOG and ADAMTSL2 as preferentially dependent on ENG and show that their transcript levels have strong positive correlation with ENG in human lung tissues; the expression levels of all three genes are significantly reduced in PAH. Our findings address an important gap in our understanding on ENG biology and provide crucial insight for therapeutic targeting these pathways in vascular diseases.

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2025-11-03 | Abstract 4373256: BMP9 drives vasoactive gene expression in endothelial cells via non-canonical ALK1-SMAD3 signaling

Rationale: The role of BMP9 in pulmonary arterial hypertension (PAH) remains controversial. Loss-of-function GDF2 /BMP9 mutations in heritable PAH suggest its function as a vascular endothelial homeostasis factor, however, modulating BMP9 signaling in experimental pulmonary hypertension (PH) models can yield pathogenic or protective effects. The impact of BMP9 upon intracellular and intercellular angiogenic signaling cascades remains poorly understood. Methods/Results: We analyzed BMP9-mediated transcription in pulmonary microvascular endothelial cells (PMVEC) derived from controls and patients, and in the presence or absence of co-cultured pulmonary artery smooth muscle cells (PASMC). We tested recombinant BMP9, BMP9/BMP10 ligand trap ALK1-Fc, anti-BMP9, and activin/GDF ligand trap ACTRIIA-Fc in hypoxia, SUGEN5416+hypoxia (SU-Hx) and monocrotaline (MCT) experimental PH rodent models. The BMP9-regulated secretome of ECs was examined for potential modulation of PASMC phenotype and function. Inhibition of BMP9 and/or BMP10 was protective whether administered before or after the development of experimental PH, and attenuated experimental PH when administered therapeutically in the SU-Hx model. In PMVEC, BMP9 elicited expression of vasoactive genes that were also elevated in experimental PH and human PAH lungs, including EDN1, CXCL12, IGFBP4, COL18A1, VEGFA, PDGFB , and SERPINE1 , several of which were normalized in lungs of SU-Hx rats with anti-BMP9 treatment. Several of these genes required non-canonical activation of SMAD3 downstream of BMPR2, ALK1, and ENG. Promoter analysis of human ET-1 revealed cooperation of SMAD3 and SMAD1/5 binding elements is required for BMP9-mediated expression of ET-1 . Co-culture models revealed the essential role of BMP9-mediated PMVEC paracrine signaling in modulating PASMC contractile phenotype markers ( CNN1 ; TAGLN ), which was attenuated by anti-CXCL12, CXCR4 antagonist, or anti-BMP9. Conclusions: BMP9 is a central regulator of vasoactive endothelial genes via ALK1-SMAD3 signaling that modulate PASMC phenotype and contribute to experimental PH.

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2026-06-26 | Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH).

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease of the pulmonary vasculature characterized by obliterative remodeling of small pulmonary arteries, leading to sustained elevation of pulmonary vascular resistance, right ventricular failure, and premature death. The diagnostic gold standard remains right heart catheterization, requiring a mean pulmonary artery pressure greater than 20 mmHg at rest, a pulmonary arterial wedge pressure of 15 mmHg or below, and a pulmonary vascular resistance exceeding 2 Wood units. PAH is an autosomal dominant disorder with markedly incomplete penetrance of approximately 20-30%, indicating that germline mutations alone are insufficient to cause disease. Disease manifestation requires additional "second hits", including chronic hypoxia, systemic inflammation, hemodynamic stress, hormonal influences, and common genetic modifiers such as single-nucleotide polymorphisms (SNPs). This genetic and environmental complexity underpins the broad clinical heterogeneity observed across PAH subtypes, which include idiopathic PAH, heritable PAH, and disease associated with connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure. This review provides a comprehensive and critical appraisal of the molecular-genetic architecture of PAH. Thirty genes have now been implicated in disease pathogenesis, spanning seven functional categories: receptors of the TGF-β/BMP signaling family (BMPR2, ACVRL1, ENG, BMPR1B); circulating BMP ligands (GDF2, BMP10); transcription factors (TBX4, SOX17, KLF4, FOXF1, SMAD1, SMAD4, SMAD9); membrane and polyamine transporters (ATP13A3, AQP1); potassium channel regulators (KCNA5, KCNK3, ABCC8); metabolic and mitochondrial genes (EIF2AK4, NFU1, GGCX); signaling receptors and structural proteins (NOTCH3, KDR, CAV1, PLEKHH2); vasoactive and extracellular matrix regulators (KLK1, CBLN2, CD248); and epigenetic regulators (TET2, TOPBP1). Among these, BMPR2 is the dominant contributor, accounting for 53-86% of heritable PAH and 14-35% of idiopathic cases. The remaining genes each account for fewer than 5% of cases individually, collectively reflecting a broad landscape of rare and ultra-rare genetic contributions. For each gene, we critically evaluate the strength of genetic evidence, pathogenic mechanisms, degree of mechanistic resolution, and clinical relevance. We further discuss the contribution of emerging technologies, including whole-genome sequencing, single-cell and spatial transcriptomics, multi-omics integration, iPSC-derived vascular models, and artificial intelligence, to expanding the PAH genetic architecture beyond single-gene discovery. A key theme across this landscape is convergence: despite mechanistic diversity at the gene level, most PAH-associated variants ultimately impair endothelial quiescence, promote smooth muscle proliferation, and drive apoptosis resistance through disruption of BMP signaling amplitude, transcriptional stability, ion channel homeostasis, metabolic integrity, or epigenetic regulation. This convergence supports both a unified therapeutic rationale and a precision medicine framework for genotype-stratified intervention in PAH.

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2026-03-28 | Cardiovascular genomics: the advanced frontier of CVD management

Cardiovascular genomics: the advanced frontier of CVD management Prof. Dr. Prabir Kumar Das FCPS, MD, FACC,FCSI Former HOD, Dept. of Cardiology, Ctg. Medical College & Secretary General, Chattogram Heart Foundation Abstract Cardiovascular genomics are specialized field that explore the role of genetics in the development and progression of cardiovascular diseases. About 10-15% of all non communicable diseases are familial and inherited conditions following Mandolin or monogenic inheritance pattern. These includes congenital heart disease, aortic and arterial disease, inherited cardiomyopathies, inherited arrhythmias and cardiac conduction defects, atrial fibrillation, familial hypercholesterolemia, systemic hypertension, pulmonary hypertension and some rare CV diseases. Understanding the genetic basis of rare and common CVDs has advanced substantially over the last 25 years. With the advent of sequencing of human genome by next generation sequencing(NGS) technique in 2000,it emerged as a preferred method of complete elucidation of genetic cause of single gene disorders .CV genomic medicine offers opportunity to review and organize management and prevention of wide ranging inherited and familial CV conditions..It encompasses personalized medicine targeting specific individuals; precision medicine targeting specific molecular disease and evidence-based medicine with most upto date top validated evidences. Several NGS based diagnostic multi-gene panels now available for confirmation of disease causing specific gene mutation or pathogenic variants in major inherited CV conditions. Genomic laboratories offer this service and developed specific genotype-phenotype databases. High risk screening allows earlier diagnosis, risk stratification, aggressive treatment and improved outcome. DNA-editing technology through application of CRISPR-Cas9 can be used to edit genes within living organisms enabling correction of monogenic conditions. For polygenic CVD whole genome sequencing at birth may allow primordial prevention with assessment of genetic determinants of lifetime risk for CVD. At present use of genomics has gone beyond screening, diagnosis and risk prediction into therapeutics. Evaluating genomic information now forms part of routine clinical workflow for inherited cardiac conditions in improving diagnostic decision-making, screening of relatives, and guiding decisions on therapy.

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2025-12-19 | Comparative outcomes of bilateral lung and heart-lung transplantation in primary pulmonary arterial hypertension: A UNOS database study.

In end-stage primary pulmonary arterial hypertension (PAH), chronically elevated pulmonary vascular resistance leads to right ventricular hypertrophy, dilation, and failure, complicating transplant decision-making. Surgical options include bilateral lung and heart-lung transplantation, but the optimal strategy remains debated. We conducted a retrospective cohort study using the Organ Procurement and Transplantation Network to identify adults (≥18 years) who underwent bilateral lung or heart-lung transplantation for PAH between June 30, 2004, and September 30, 2022. Patients with congenital or structural cardiac abnormalities were excluded. Baseline demographics, comorbidities, hemodynamics, perioperative course, and survival were compared by transplant type. The primary outcome was 1-year mortality; the secondary outcome was 5-year mortality. Of 914 PAH recipients, 776 (84.9%) underwent bilateral lung transplantation and 138 (15.1%) underwent heart-lung transplantation. Bilateral lung recipients had higher cardiac index (2.4 vs 2.2 liter/min/m², p = 0.02) and lower pulmonary capillary wedge pressure (11 vs 13 mm Hg, p < 0.001). They were more likely to require extracorporeal membrane oxygenation at 72 hours (24.2% vs 10.8%, p = 0.02) and remain intubated (43.0% vs 23.9%, p < 0.001). Survival was similar between groups. Heart-lung transplantation was not associated with increased mortality at 1 year (adjusted hazard ratio 1.82, 95% cardiac index 0.89-3.71, p = 0.10) or 5 years (hazard ratio 1.49, 95% cardiac index 0.87-2.54, p = 0.14). Findings were consistent across hemodynamic subgroups. In PAH, bilateral lung transplantation achieves comparable 1- and 5-year survival to heart-lung transplantation, supporting its role as a viable alternative in appropriately selected patients.

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2025-12-17 | Generation of 5 hiPSC lines from pediatric patients with Heritable pulmonary arterial hypertension (HPAH) caused by heterozygous mutations in the TBX4 gene.

Heritable pulmonary arterial hypertension (HPAH) and underlying pulmonary vascular disease (PVD) are often caused by TBX4 mutations-either loss- or gain-of-function-which are a leading cause of childhood-onset PAH. The clinically heterogeneous TBX4 syndrome can include skeletal anomalies (e.g., small patella syndrome) and developmental lung disease (DEVLD) (Galambos, 2019). TBX4 is expressed in lung mesenchymal cells such as matrix fibroblasts, pericytes, and smooth muscle cells, all contributing to PAH pathogenesis (Karolak, 2023; Maldonado, 2025). Our five patient-derived TBX4-mutant hiPSC lines provide a powerful model to investigate cell-specific mechanisms in HPAH/DEVLD-PH and support precision drug discovery and therapy development targeting TBX4-related abnormalities.

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2025-11-03 | Abstract 4363073: Somatic activating mutation in Phosphoinositide 3-kinase in a plexiform lesion of a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension

Background: Hereditary hemorrhagic telangiectasia (HHT) and hereditary pulmonary arterial hypertension (HPAH) are genetic diseases that affect the pulmonary vasculature. HHT and HPAH are due to a haploinsufficiency in components of the bone morphogenetic protein receptor type 2 (BMPR2) pathway. Despite shared genetics, HHT and HPAH cause different pulmonary vascular lesions. In HHT, pulmonary arteriovenous malformations (pAVMs) can occur. These are abnormal shunts between arteries and veins that can lead to stroke. HPAH is characterized by extensive remodeling of the lung including the formation of plexiform lesions, convolutes of vascular channels that were described as a pathological hallmark of PAH. The pathobiology of pAVMs and plexiform lesions is incompletely understood. Recent studies suggest that a local bi-allelic loss of HHT causing genes in clonally expanding endothelial cells (ECs) might be required for AVMs to form in patients with HHT. In plexiform lesions, clonal EC expansion was also described. Hypothesis: We hypothesized that local somatic mutations in ECs might be involved in the pathogenesis of pulmonary vascular lesions in HHT and HPAH. Aims: We here aimed at detecting somatic mutations in pulmonary vascular lesions of a patient with HHT and end-stage PAH caused by a mutation in ENG . Methods: Targeted deep sequencing of 3 HHT causing genes and 11 vascular malformation associated genes was performed on 4 pAVMs and 14 plexiform lesions of the patient. Results: The disease-causing germline mutation in ENG was detected in every sample. No somatic mutation in the functional allele of ENG was detected in the pulmonary vascular lesions. However, we identified a somatic mutation in the gene encoding for Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Alpha ( PIK3CA) in one of the plexiform lesions. This mutation is a confirmed activating somatic mutation in the Catalogue Of Somatic Mutations In Cancer that was previously functionally confirmed as a moderately potent oncogenic mutation. Conclusion and Outlook: We here describe a rare case of an ENG mutation carrier with HHT and HPAH. We identified a somatic activating mutation in PIK3CA in one of her plexiform lesions. To explore if the mutation contributes to the overgrowth of ECs in a plexiform lesion on a background of a haploinsufficiency in ENG , we are performing functional studies on iPSC-derived ECs from this patient after introduction of the mutation in PIK3CA by Crispr/Cas9.

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