PTEN suppresses epigenetic modulation of ERG transcription factor to maintain endothelial lineage and vascular integrity

Abstract

Homeostatic replenishment of endothelial cells (ECs) after injury is required for the efficient formation of a stable endothelial lineage and to prevent long‐lasting lung vascular injury such as protein‐rich edema in the interstitial tissue, a hallmark of tissue inflammation. However, mechanisms maintaining EC lineage remains unclear. Phosphatase and tensin homologue (PTEN), a tumor suppressor, is well‐known to function in cell membrane to negatively regulate PIP3 levels required for angiogenesis and endothelial cell proliferation and thereby may have role in regulating EC fate. Thus, we induced the conditional deletion of PTEN in ECs of adult mice using tamoxifen to address the hypothesis that PTEN regulates EC lineage. Intriguingly, we found that EC‐specific loss of PTEN led to intractable vascular injury basally due to marked reduction in EC number in the lung. FACS analysis showed that these ECs acquired fibroblast‐like phenotype. RNA seq analysis of PTEN depleted ECs showed PTEN was required for maintaining ECs genes including VE‐cadherin and PECAM. PTEN maintained ECs genes by activating ETS (E26 Transformation Specific) family member transcription factor, ERG. We show that this function of PTEN occur in nucleus since loss of PTEN increased the activity of epigenetic modulating gene, HDAC1 leading to upregulation of non‐EC genes and thereby converting these ECs into fibroblasts like cells. Inhibition of HDAC1 activity by velproic acid and trichostatin rescued ERG expression and transcription of VE‐cadherin in PTEN depleted cells. Thus, we identify a novel role of PTEN in suppressing HDAC1 activity enabling thereby ERG transcription of EC genes leading to EC generation and lung‐vascular homeostasis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.