National Heart, Lung, and Blood Institute 2P01HL146369-07

TGF-ß-SOX18-Collagen metabolism in pulmonary vascular disease associated with CHD

This award funds research on the role of SOX18 and TGF-β signaling in pulmonary vascular disease associated with congenital heart defects, focusing on metabolic changes and collagen production contributing to pulmonary artery stiffness and potential therapeutic interventions.

Description

Children born with common congenital heart defects that cause increased pulmonary blood flow (PBF) develop abnormal pulmonary vascular reactivity and, if untreated, pulmonary hypertension (PH). Vascular morphology studies in lambs born with surgically created left-to-right shunts (Shunt) demonstrate a >2-fold increase in pulmonary arterioles and increased proximal pulmonary artery (PA) stiffness. While this increase in angiogenesis represents an early adaptation to increased PBF and is not typically observed in adults with late-stage disease, proximal PA stiffness is common to all PH and is a driver of disease pathogenesis. Metabolic rewiring is a unifying endothelial feature in PH. Pulmonary arterial endothelial cells (PAEC) isolated from Shunt lambs exhibit significant metabolic rewiring to favor a Warburg phenotype supporting angiogenesis. SOX18, an endothelial-specific transcription factor, is upregulated in Shunt lambs and induces an angiogenic response. The hypothesis is that SOX18 triggers early metabolic adaptation, leading to aerobic glycolysis and increased proline biosynthesis necessary for angiogenesis and collagen production, contributing to MPA stiffness. The study will evaluate the role of TGF-β signaling in inducing SOX18 and its regulation of Phd2 gene expression, HIF-2-mediated proline biosynthesis, and fatty acid oxidation disruption via PPARγ inhibition. Therapeutic potential of inhibiting SOX18 or collagen synthesis will be tested using propranolol and Cmpd17.

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