Defense Date

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy

Department

Physiology and Biophysics

First Advisor

Laszlo Farkas

Second Advisor

Roland Pittman

Third Advisor

John Ryan

Fourth Advisor

Fadi Salloum

Fifth Advisor

Daniel Conway

Abstract

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.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-13-2021

Available for download on Tuesday, May 12, 2026

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