Role of P53 Deficient Clonogenic Endothelial Cells in the Pathogenesis Of Pulmonary Hypertension
Doctor of Philosophy
Physiology and Biophysics
Pulmonary Artery Hypertension (PAH) is a progressive disorder of the small vessels of the pulmonary vasculature. It is characterized by occlusive vascular remodeling leading to right heart failure and ultimately death. PAH pathogenesis involves a multifactorial etiology leading to formation of occlusive lesions in small (preacinary) pulmonary arteries. These lesions contain hyper-proliferative, apoptosis resistant endothelial cells (ECs), smooth muscle cells and fibroblasts. ECs play a major role in the development of PAH. These ECs in vascular lesions are primitive and express progenitor cell markers, including CD117 (c-kit).
We have isolated clonally expanded, c-kit+ ECs from the lungs of Green Fluorescent Protein (GFP+) transgenic rats. These ECs expressed progenitor cell markers and are highly proliferative and angiogenic with reduced p53 levels. Additionally, these cells showed the ability to undergo endothelial to mesenchymal transition (EndMT) driven by transforming growth factor (TGF)-β and reduction in bone morphogenic protein (BMP) signaling. TGF-β inhibition in transitioned clonal cells restored EC function via elevated BMP signaling.
Transplantation of clonal cells to hypoxia-exposed rats reduced p53 levels in rat lungs along with elevation of the RVSP and formation of occlusive lesions. These effects were reversed by treatment with the Mouse Double Minute 2 Homolog (MDM2) blocker Nutlin 3a. Furthermore, treatment of ECs from PAH patients with Nutlin 3a increased p53 levels and reduced angiogenic network formation.
Our findings demonstrate the role of p53 in the pathogenesis of PAH and suggest pharmacological elevation of p53 by Nutlin 3a as a promising therapeutic option.
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Available for download on Tuesday, May 12, 2026
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