Requirement of Mef2 Transcriptional Factors in Maintaining Vascular Integrity

Abstract

Purpose: : Maintenance of vascular endothelium integrity is critical for the development and homeostasis of the vascular system. The goal for this study is to unravel the mechanisms whereby endothelium integrity regulated by endothelial cells (ECs) at the transcriptional level.

Methods: : The function of MEF2 transcriptional factors in vascular ECs is studied using in vivo knockout mice and in vitro cell culture models.

Results: : We show that MEF2 transcription factors, originally identified as regulators of muscle development, are required for regulating vascular integrity in vivo. Target deletion of MEF2C and MEF2D specifically in ECs in mice leads to vessel leakiness, hemorrhaging and perinatal lethality, due to loss of vascular integrity. Adenovirus overexpression of MEF2-engrailed super-repressor inhibits angiogenesis in vitro. These ECs appear normal but undergo extensive cell death when cultured under hypoxia condition. Moreover, these cells are defective in VEGF induced migration.

Conclusions: : Our results reveal a critical, EC-autonomous role for MEF2 transcription factors in maintaining vascular integrity, especially under stress conditions. Manipulating MEF2 activity in ECs may have significant therapeutic potential for treating various vascular diseases. The targets of MEF2 in EC and their mechanisms of action will be discussed.

Keywords: apoptosis/cell death • genetics • transcription factors