The Role of Endothelial Dysfunction and Vascular Inflammation in Hypertensive Vascular Remodeling

Temple Univ Of The Commonwealth, Philadelphia PA

Investigators

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Abstract

Project Summary Hypertension (HTN) is a pathophysiological condition promoting unfavorable vascular complications resulting in decreased quality of life, and increased risk of developing other cardiovascular diseases. Angiotensin II (AngII) plays a key role in the development of hypertensive vascular inflammation and downstream damage including hypertrophy, fibrosis, and endothelial dysfunction. Interestingly, mitochondrial dysfunction and endoplasmic reticulum stress (ER stress) are implicated in AngII-induced vascular dysfunction. However, how these two organelles communicate and mediate vascular inflammation is unknown. DRP1 is a regulator of mitochondrial fission and is implicated in cardiovascular pathologies. As well, CHOP is implicated as a key mediator in the ER stress response. The proposed research design focuses on AngII-induced EC inflammatory activation through mitochondrial and ER stress and how DRP1 and CHOP mediate this response. Our preliminary data strongly suggest a critical role for mitochondrial dysfunction and ER stress in AngII-induced vascular inflammation and dysfunction. The long-term research goal is to elucidate novel insight into the complexity of HTN and associated vascular dysfunction/remodeling and how endothelial inflammation contributes to vascular health. Additional interest is focused on DRP1 and CHOP dependent mechanisms of vascular inflammation by contributing to mitochondria and ER signaling. The specific aims are as follows: (1) To explore how mitochondria and ER signaling contribute to vascular inflammation in response to AngII in vitro. (2) To explore how endothelial DRP1 contributes to vascular inflammation and hypertensive vascular remodeling in vivo. Specific aim 1 will be conducted using pharmacological and genetic blockade of DRP1 in AngII treated ECs to assess the contribution of DRP1 in mitochondrial dysfunction, ER stress and inflammation in human ECs. Additionally, blockade of CHOP will be used to establish role for CHOP in mitochondrial dysfunction and inflammatory activation. Specific aim 2 will be conducted using tamoxifen-inducible endothelial specific DRP1 knockout mice treated with AngII in order to study the EC-specific role of DRP1 in vascular inflammation and cardiovascular remodeling. Accomplishment of specific aims will provide a novel understanding of organellular communication between the mitochondria and the ER in the setting of HTN and how this can mediate vascular inflammation and remodeling. In terms of public health, treatment of hypertensive end-organ damage through a reduction in inflammation provides a novel translational approach in treating HTN and vascular complications.