METABOLIC REPROGRAMMING AND PULMONARY VASCULAR DISEASE ASSOCIATED WITH CONGENITAL HEART DISEASE RESULTING IN INCREASED PULMONARY BLOOD FLOW

Florida International University, Miami FL

Investigators

Linked publications & trials

Abstract

PROGRAM SUMMARY Pulmonary vascular disease (PVD) is one of the most critical complications of children born with congenital heart disease (CHD) that results in increased pulmonary blood flow (PBF). Metabolic reprogramming is increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular morphology studies in our model demonstrate a >2-fold increase in pulmonary arterioles in Shunt compared to control lambs. This is opposed to decreased arterial counts in humans with advanced disease. This early increase in angiogenesis represents an adaptation to increased PBF. Developing a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this angiogenic response and requires a dramatic metabolic reprogramming that supplies these cells with the requisite biosynthetic precursors. A consequence of these metabolic changes is the loss of NO signaling, the development of endothelial dysfunction, and increased vascular remodeling. We will extend our investigations into a new metabolic pathway—proline biosynthesis and collagen deposition—in this competitive renewal. This will significantly boost the impact on three levels: first, mechanistically, the proline- collagen axis is receiving renewed interest in the PVD field, but little is known of its role in the endothelium; second, functionally, collagen is a critical regulator of cell proliferation, survival, and angiogenesis; and third, pathologically, changes in collagen alter the mechanical properties of the vessel leading to increased stiffness. Proximal pulmonary artery stiffness is increasingly recognized as an early marker of advancing PVD. Overall, this PPG will continue to focus on increasing our understanding of i) the transcription factors that drive the metabolic rewiring of pulmonary endothelium, ii) post-translational modifications (PTMs) that influence metabolic reprogramming, iii) interactions between mitochondrial network dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. These represent the thematic underpinning of this PPG. Project 1 will investigate the paradigm-shifting hypothesis that the mechanically regulated transcription factor, SOX18, metabolically rewires the endothelium to stimulate proline biosynthesis, leading to collagen deposition and increased vascular stiffness. Project #2 will continue to build on ongoing studies investigating the role of mitochondrially localized pp60Src and PTM-mediated regulation of cellular energetics. Project #3 will continue investigating the role of disrupted mitochondrial network dynamics in developing PVD, focusing on persistent MFN2 loss in a metabolic reprogramming favoring glutamine-proline metabolism. Each project, along with the supporting scientific Cores, will focus on integrated and synergistic investigations to continue to increase our understanding of how the metabolic rewiring of the pulmonary endothelium leads to the hyperproliferative, anti- apoptotic angiogenic EC phenotype, the loss of NO signaling, endothelial dysfunction, and vascular remodeling.