Biology subjects

Yu, P. B.

Publications and source records attributed to Yu, P. B..

7 recordsLinked to original sources

bioRxiv2026

Physiological Aging and Cardiovascular Disease Distinctly Remodel the Human Cardiac Lymphatic Endothelium

Aims: Cardiac lymphatic endothelial cells (LECs) regulate tissue homeostasis, immune trafficking, and remodeling, but how human cardiac LEC heterogeneity changes with physiological aging and cardiovascular disease remains poorly defined. We sought to define age- and disease-associated LEC states, their regulatory and microenvironmental programs, and the functional relevance of selected pathways. Methods and results: We integrated human cardiac single-nucleus transcriptomic datasets spanning physiological aging, dilated and hypertrophic cardiomyopathy, doxorubicin-associated cardiomyopathy, and heart failure with preserved ejection fraction. Aging redistributed LECs among pre-existing states, with expansion of a homeostatic immune-surveillance state and loss of cytokine-responsive and polarity-associated states. Cardiovascular diseases showed a distinct trajectory, with depletion of a non-failing homeostatic state and expansion of shared and disease-associated remodeling states. SCENIC and NicheNet/MultiNicheNet identified state-specific regulatory programs and disease-dependent signaling networks, with recurrent BMP/TGF-{beta}/activin-family signaling. ACVR2A was prioritized in human doxorubicin-associated cardiomyopathy; endothelial Acvr2a deletion in aged doxorubicin-treated mice was associated with improved cardiac function and increased open cardiac lymphatic vessels. Independent human spatial transcriptomic analyses supported selected aging- and disease-associated programs. Conclusion: Physiological aging and cardiovascular disease remodel cardiac LECs through distinct changes in cellular state, transcriptional regulation, and microenvironmental signaling. Aging is associated with redistribution and reduced representation of specialized LEC programs, whereas cardiovascular diseases redirect LECs through disease-associated signaling environments, highlighting context-dependent remodeling of the cardiac lymphatic endothelium across aging and disease.

bioinformatics↗

bioRxiv2025

BMP9-mediated regulation of endothelin-1 requires integrated SMAD1/5 and SMAD2/3 signaling

BMP9 is a pleiotropic growth factor cytokine with diverse roles in vascular development, homeostasis and disease. BMP9 regulates a broad array of vasoactive molecules that mediate endothelial and mural cell function, including ET-1, a potent vasoconstrictor, regulator of cell growth and fibrosis, and therapeutic target for pulmonary arterial hypertension (PAH). Consistent with its pleiotropic activities, BMP9 is unique in being able to recruit both BMP-responsive SMAD1/5/9 and TGF{beta}-responsive SMAD2/3 signaling effectors in endothelial cells, however, the physiologic significance of activating both pathways remains incompletely defined. We investigated the role of SMAD1/5/9 vs. SMAD2/3 signaling in BMP9-mediated regulation of ET-1, using primary and immortalized human and murine microvascular endothelial cells, with conditional knockout, small molecule inhibitor and siRNA strategies. BMP9-mediated expression of ET-1 requires coordinated activation of SMAD1/5/9 and SMAD2/3 effector pathways, both downstream of BMPR2, ALK1, and ENG. Analysis of the ET-1 promoter revealed that BMP9 requires, in addition to a SMAD3/4 binding site sufficient for TGF{beta}1-mediated transcription, a novel putative SMAD1/5 binding motif. BMP9-mediated regulation of endothelial ET-1 requires coordinated activation of both SMAD1/5 and SMAD2/3 downstream of ALK1, integrated at the promoter level, representing a non-canonical signaling motif linking BMP9 to a critical effector of vascular tone and remodeling in PAH and related vascular syndromes. Translational PerspectiveBMP9 has recently emerged as a novel therapeutic target with an ongoing Phase 2 clinical trial testing an anti-BMP9 antibody for efficacy in PAH (NCT06137742). The mechanisms by which BMP9 contributes to pulmonary vascular disease are thought to include its regulation of Endothelin-1 (ET-1), an established therapeutic target in PAH. We show that BMP9 potently regulates ET-1 transcription via transactivation of TGF{beta}1 effector SMAD3 via BMP receptors BMPR2 and ALK1, suggesting that pleiotropic effects of this growth factor cytokine result from non-canonical activation of BMP and TGF{beta} signaling pathways, with implications for its roles in physiology, and the rationale for its therapeutic modulation for PAH.

cell biology↗

bioRxiv2025

BMP9 regulates the endothelial secretome to drive pulmonary hypertension

BMP9, a pleiotropic growth factor cytokine that regulates endothelial function, is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Loss-of-function mutations in GDF2 are found in heritable PAH, suggesting its function as an endothelial quiescence factor, while agonizing or antagonizing BMP9 signaling are both reported to ameliorate experimental pulmonary hypertension (PH). This study sought to resolve the contribution of BMP9 to pulmonary vascular disease and its status as a potential therapeutic target. The function of BMP9 in experimental PH was interrogated using recombinant BMP9, BMP9/BMP10 ligand trap ALK1-Fc, two anti-BMP9 neutralizing antibodies, and the activin/GDF/BMP ligand trap ACTRIIA-Fc (a.k.a., sotatercept). Disulfide-linked, prodomain complexed BMP9 was not protective in SUGEN-hypoxia or monocrotaline-induced PH models, in contrast to previous studies using incompletely disulfide-linked BMP9. In comparison, selective and non-selective BMP9 antagonism exerted prophylactic and therapeutic effects across PH models. Anti-BMP9 and ACTRIIA-Fc had comparable impact on hemodynamics, RV hypertrophy, and vascular remodeling, while single nucleus RNA-Seq revealed similar inhibition of SMAD1/5 and SMAD2/3 transcriptional activity, and highly overlapping DEGs, particularly in the endothelial compartment (r=0.83, p=2.54e-43, Spearman), suggesting overlap of mechanism in targeting BMP9. A multi-omic approach using lung tissues from human PAH, experimental models of pulmonary hypertension, and transcriptomic analysis of pulmonary microvascular endothelial cells from PAH patients revealed that BMP9 is critical for regulating several endothelial gene products that are overexpressed in human and experimental disease and implicated in disease pathogenesis including CXCL12, PDGF-BB, EDN1, COL18A1, and IGFBP4, and are inhibited by administering anti-BMP9 neutralizing antibodies or ligand traps. Co-culture studies revealed paracrine effects of BMP9-stimulated PMVEC on pulmonary arterial smooth muscle cell (PASMC) phenotypic plasticity, which could be attributed in large part to endothelial-derived CXCL12. In summary, endothelial BMP9 signaling is a key coordinator of vasoactive endothelial gene products that modulate PASMC phenotype and appears to be a shared target of anti-BMP9 and ACTRIIA-Fc. Selective targeting of endothelial BMP9 angiogenic signaling represents a potential therapeutic strategy for human PAH. One sentence summaryInhbiition of BMP9 signaling via different selective and non-selective strategies, including ACTRIIA-Fc/sotatercept, attenuates endothelial expression of vasoactive secreted factors that drive pulmonary vascular remodeling.

physiology↗

bioRxiv2025

Cross-species analysis of experimental PH at single cell resolution reveals prominent contributions Ednrb+ EC and Dhcr24+ macrophage populations

BackgroundAnimal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompletely defined. Materials and methodThis study analyzed the relationship between several rodent models of PH and human disease at single-cell resolution. scRNA-seq was performed on lungs from mice exposed to hypoxia or Sugen/hypoxia, rats exposed to monocrotaline, and controls. A cross-species single-cell dataset was integrated with human lung cell atlas (HLCA) and single-cell dataset from idiopathic pulmonary arterial hypertension (IPAH) to identify overlapping cell subsets between experimental and human disease and species. ResultsHigh levels of overlap were found between species and models of PH, HLCA, and IPAH datasets. Cell subsets perturbed in rat and mouse PH were similar to those found in human disease, with macrophages and endothelial cells being most affected. A novel Dhcr24high macrophage subset harboring both tissue-remodeling and pro- inflammatory features was consistently increased across models. Several functionally diverse endothelial subtypes were found, including novel Ednrb+ and Nox2+ subpopulations, reflecting enhanced apoptosis, dysregulated angiogenesis and proliferation, and reactive oxygen species-mediated stress. These macrophage and endothelial subtypes expressed numerous PH drug target genes, and exhibited potential disease-specific intercellular interactions involving Angptl4, Cxcl12, and Sema3 signaling. Disease-associated changes in these populations were confirmed by immunofluorescence in lung tissues from animals and patients. ConclusionsWe established a comprehensive cross-species single-cell atlas of mainstream rodent PH models, highlighting several novel macrophage and endothelial subtypes and signaling motifs potentially contributing to human disease.

bioinformatics↗

bioRxiv2021

ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, Activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by Activin A, an effect countered by inhibition of Activin A via monoclonal antibody treatment. Hence, we surmised that ACVR1 antibodies that block activation of ACVR1 by ligand should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated ACVR1 monoclonal antibodies that block ACVR1s activation by its ligands. Surprisingly, in vivo, these ACVR1 antibodies stimulate HO and activate signaling of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1 and results from ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild type ACVR1 is inhibited by ACVR1 antibodies. These results uncover an additional novel property of FOP-mutant ACVR1 and indicate that ACVR1 antibodies should not be considered as therapeutics for FOP.

biochemistry↗

bioRxiv2020

Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues due to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2/ACVR1. From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2 compared with other receptors of the BMP/TGF{beta} signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D transgenic mouse line, which provides a model of heterotopic ossification, as well as an inducible ACVR1R206H knock-in, which serves as a genetically and physiologically faithful model of FOP. In both models, saracatinib was well tolerated and potently inhibited the development of heterotopic ossification even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in the treatment of FOP, offering an accelerated path to clinical proof of efficacy studies and potentially significant benefits to individuals with this devastating condition.

molecular biology↗

bioRxiv2020

Circulating BMP9 protects the pulmonary endothelium during inflammation-induced lung injury in mice

RationalePulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome (ARDS), which carries a high mortality. Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. ObjectiveTo determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during lipopolysacharride (LPS)-induced lung inflammation and permeability. MethodsA BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human primary lung endothelial cells. Impact of BMP9 was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Main ResultsSubacute neutralization of endogenous BMP9 in mice resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In lung endothelial cells, BMP9 regulated a programme of gene expression and pathways controlling vascular permeability and cell membrane integrity. Augmentation of BMP9 signalling in mice with exogenous BMP9 prevented inhaled LPS-caused lung injury and edema. In endotoxemic mice, endogenous BMP9 levels were markedly reduced, due to a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human sepsis patients, circulating levels of BMP9 were also markedly reduced. ConclusionsEndogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Supplementation with exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in the setting of lung injury. Short summaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSIncreased pulmonary endothelial permeability is a major factor in the development of acute respiratory distress syndrome (ARDS). Evidence is emerging that circulating BMP9, secreted from the liver, might protect the pulmonary endothelium from injury. For example, loss of BMP9 levels or signalling receptor contributes to the development of pulmonary arterial hypertension. The role of endogenous BMP9 in endothelial permeability remains unclear. What This Study Adds to the FieldHere we show that subacute neutralization of endogenous BMP9 leads to lung vascular injury, including enhanced permeability and neutrophil extravasation. BMP9 levels were markedly reduced in the setting of inflammation in mice and humans. Conversely, exogenous supplementation of BMP9 protected the lung from LPS-induced injury. This study suggests that exogenous BMP9 could offer a novel approach to prevent increased pulmonary endothelial permeability in the setting of lung injury and ARDS.

physiology↗