Biology subjects

Woodcock, C.-S. C.

Publications and source records attributed to Woodcock, C.-S. C..

3 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte NLRP3 signaling in right heart failure is sexually dimorphic via estrogen receptor α

RationaleRV adaptation in pulmonary hypertension is sexually dimorphic and more preserved in women. NLRP3 inflammasome activation contributes to RV failure (RVF) development. However, regulators and downstream effects of NLRP3 activation in the RV remain unknown. ObjectivesWe investigated whether NLRP3 inflammasome activation in RVF is sexually dimorphic, whether NLRP3 is active in RV cardiomyocytes (RVCMs) and causes RVCM contractile dysfunction, and whether 17{beta}-estradiol (E2) and its receptor ER attenuate this process. MethodsWe studied RV tissues from PAH patients with RVF, RV tissues and RVCMs isolated from wild-type and ER loss-of-function mutant rats with RVF, isolated perfused rat hearts, and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. NLRP3 activation was assessed via RNA-sequencing, proteomics, immunostaining, and downstream target quantification. RV contractility was assessed via pressure-volume loops, perfused heart studies, and contractility and calcium assessments in isolated RVCMs. Measurements and Main ResultsNLRP3 was upregulated in RVCMs during RVF and resulted in altered RVCM calcium handling and RVCM contractile dysfunction. In human RVs, hiPSC-cardiomyocytes and rat RVs, NLRP3 activation and NLRP3-induced RVCM contractile dysfunction were sexually dimorphic and male-biased. Ovariectomy and loss of ER in females eliminated this sex bias. E2, via ER, prevented RVCM NLRP3 activation and NLRP3-induced RVCM contractile dysfunction in males and ovariectomized females during both acute and chronic RV pressure overload. ER directly interacted with NLRP3. ConclusionsNLRP3-driven RVCM contractile dysfunction is male-biased. E2 inhibits NLRP3 through ER to preserve RVCM contractility. Targeting E2-ER-NLRP3 signaling may offer novel therapeutic strategies for RVF in low estrogen states. ImpactThis is the first study to define a novel estradiol-estrogen receptor -NLRP3 axis that modulates RV cardiomyocyte function and RV adaptation in pulmonary hypertension. We demonstrate for the first time that NLRP3 activation is therapeutically targetable in low estrogen states via NLRP3 inhibitors or 17{beta}-estradiol. These findings have direct implications for therapeutic strategies aimed at preserving or restoring RV contractile function in pulmonary hypertension, a current area of unmet clinical need.

molecular biology↗

bioRxiv2025

Sexually dimorphic role of estrogen receptor α in preserving right ventricular endothelial integrity

Right ventricular (RV) function and adaptation to afterload increase determine survival in pulmonary hypertension (PH). RV adaptation in PH is sexually dimorphic and more preserved in females, mediated by protective estrogen receptor (ER) signaling in cardiomyocytes. However, the effects of ER on RV endothelial cells (RVECs), a critical mediator of RV homeostasis and adaptation, are unknown. We hypothesized that ER exerts sexually dimorphic pro-angiogenic effects on RVECs in vitro and promotes RV vascularization in vivo. Compared to cells isolated from wild-type animals, RVECs from male and female rats with an ER loss-of-function mutation (ERMut) showed reduced ability to form pseudo-vascular networks and migrate. RVECs from female ERMut rats demonstrated increased apoptosis. In a PH model induced by monocrotaline (MCT), female ERMut rats exhibited increased RV hypertrophy and reduced RV capillary density before (10 days) and at the time of established PH (28 days). Capillary rarefaction was associated with increased RVEC apoptosis, and, as identified by single-nucleus RNA-sequencing, by a net loss of the endocardial RVEC sub-population. Differentially expressed gene analysis and pathway analysis identified that capillary and endocardial RVECs from female MCT-PH ERMut rats demonstrated decreased expression of migration pathways and increased expression of apoptosis pathways. These findings reveal a sex-specific endothelial-intrinsic role of ER that is essential for angiogenesis in the RV under both homeostatic and pathological conditions. This effect appears to stem from the enhanced survival and migration capacity of capillary and endocardial RVEC. Collectively, our results identify ER as a potential target for developing sex-specific RV-directed therapies in PH. Translational perspectiveEffects of ER on vascular function in RV failure induced by PH are poorly understood. We unveiled a novel sexually dimorphic role of ER in regulating RV vascularization and RVEC function. Single nucleus RNA-Sequencing in female wild-type and ER loss-of-function rats with PH identified 5 unique RVEC sub-populations under transcriptional control of ER. Our findings provide insights into previously undescribed pro-angiogenic, pro-migratory and anti-apoptotic roles of ER in female RVs and RVECs. Promoting RVEC migration or inhibiting RVEC apoptosis to enhance RV angiogenesis may be viable pathways to maintain RV function in PH patients of either sex. These findings offer novel opportunities and potential therapeutic avenues for preventing or treating RV failure.

cell biology↗

bioRxiv2024

Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease. One Sentence SummaryPulmonary arterial hypertension pathophenotypes arise from allele-specific NCOA7 regulation of lysosome function and inflammatory oxysterol generation, as demonstrated by genomic and metabolomic association studies coupled with genetic and pharmacologic mechanistic evidence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/582142v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@896f6forg.highwire.dtl.DTLVardef@f31c2eorg.highwire.dtl.DTLVardef@bf46dcorg.highwire.dtl.DTLVardef@1c55686_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. C_FIG

physiology↗