Biology subjects

Oh, S. P.

Publications and source records attributed to Oh, S. P..

3 recordsLinked to original sources

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↗

bioRxiv2020

Hippocampal GABA-inhibitory circuitry regulates despair-like behavior in mice

Despair is a common human feeling characterized by the loss of hope and is a core symptom of depressive disorders. However, little is known regarding neural circuits mediating despair and their modulation by antidepressants. Here we show that alterations in inhibitory synaptic transmission in the hippocampus affect behavioral despair in mice. Reduced interneuron density, knockdown of GABAA receptor gamma 2 subunit gene (Gabrg2) or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Similarly, a low dose of pentylenetetrazol, a GABAAR antagonist, induced transient anti-despair-like behaviors, with rapid eukaryotic elongation factor 2 (eEF2) activation in the hippocampus. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons induced despair-like behaviors. The antidepressant ketamine rapidly increased c-Fos expression in CA1 neurons and induced anti-despair-like behaviors. These results suggest that the enhanced hippocampal CA1 neuron activity induces anti-despair-like behaviors and contributes to the antidepressant effects of ketamine.

neuroscience↗

bioRxiv2019

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1-ENG-Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K-Akt-mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine-kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs--including in HHT patient blood outgrowth ECs--and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in HHT patients.

cell biology↗