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

Florida International University, Miami FL

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Abstract

ABSTRACT 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. While a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for angiogenesis, the primary drivers of MPA stiffness in PH are ill-defined. 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 that supports the biosynthetic demands of angiogenesis. However, the inciting pathways have yet to be elucidated, and how they contribute to vascular remodeling remains unknown. We have further demonstrated that the endothelial-specific SOXF family transcription factor (TF), SOX18, is upregulated in Shunt lambs. SOX18 induces an angiogenic response in the lung, and the SOXF family can regulate PAEC metabolism. Thus, SOX18 signaling is an attractive therapeutic target, although transcription factors are typically difficult to drug. Our novel hypothesis is that SOX18 induction triggers an early metabolic adaptation, resulting in aerobic glycolysis and increased proline biosynthesis necessary for the angiogenic EC phenotype and the collagen production required for MPA stiffness. We also hypothesize that upstream TGF-β signaling is responsible for the induction of SOX18 in Shunt lambs and that SOX18 directly represses Phd2 gene expression to drive HIF-2-mediated proline biosynthesis and the disruption of fatty acid oxidation (FAO) via PPARγ inhibition. This hypothesis will be evaluated in three interrelated but independent Specific Aims (SAs). SA#1 will define the role of the TGF-β-SOX18-Proline axis in developing the angiogenic phenotype and collagen production associated with increased PBF. SA #2 will define the novel role of SOX18 in HIF-2α- mediated metabolic reprogramming in shunt PAEC. SA #3 will evaluate the therapeutic potential of directly inhibiting SOX18 activity or collagen production via novel approaches. We will use two intervention strategies. First, a prevention model in which therapy is delivered chronically for 4 weeks starting immediately after birth; second, a reversal study in which therapy is delivered in a novel post-shunt closure model mimicking surgical correction of the underlying heart defect. We will evaluate propranolol, recently identified as a specific SOX18 inhibitor, or Cmpd17, a novel small molecule collagen synthesis inhibitor we developed. These studies will yield new mechanistic insights into the role of SOX18 signaling in developing pulmonary vascular disease and highlight this TF as a druggable site for therapeutic intervention in children born with congenital heart disease that results in increased PBF.