Novel Heparin Receptor Transmembrane Protein 184A is Involved in Maintaining Proper Endothelial Cell Responses to Laminar Flow

Abstract

Endothelial cells (ECs) comprise the innermost layer of blood vessels and serve numerous critical roles in the vasculature, including nutrient delivery, gas exchange, leukocyte trafficking, and immunological surveillance. Additionally, ECs of blood vessels are constantly exposed to fluid shear stress (FSS) in the form of blood flow, and maintain vessel tone by sensing and responding to FSS through a process called mechanotransduction. Mechanotransduction in ECs is a complex biological process that involves several key adherens junction proteins, such as PECAM‐1, VE‐cadherin, and the vascular endothelial growth factor (VEGF) receptor, VEGFR2. There also exist many other proteins that act as co‐factors to regulate mechanotransduction, such as integrins and heparan sulfate proteoglycans (HSPGs). ECs typically respond to the mechanical forces of laminar (normal) FSS by aligning in the direction of flow, elongating, and maintaining communication at adherens junctions between cells. These responses constitute endogenous atheroprotective mechanisms that ECs use to prevent abnormal vascular physiology. Additionally, regions of the vasculature exposed to laminar blood flow have higher levels of the vasodilator nitric oxide (NO), an important vascular signaling molecule that is produced by endothelial nitric oxide synthase (eNOS). Improper mechanosensing, combined with chronic inflammation or disturbed FSS, can lead to EC dysfunction, which accumulates over time and results in the progression of vascular diseases such as atherosclerosis. Our laboratory recently identified Transmembrane Protein 184A (TMEM184A) as a heparin receptor in vascular cells. Moreover, we have since found that TMEM184A is a modulator of vascular regeneration in vivo. Here, we present evidence that TMEM184A is also involved in EC responses to FSS that prevent dysfunction. Immunofluorescence and immunoprecipitation data collectively suggest that TMEM184A colocalizes and interacts with the classical mechanosensors, several of the HSPGs, and eNOS on the surface of static ECs. Under laminar FSS, TMEM184A colocalization with VE‐cadherin and VEGFR2 is even more apparent. Degradation of endogenous heparan sulfates with heparinase drastically changes typical EC responses to laminar FSS by altering the normal pattern of TMEM184A accumulation in response to shear and impairing EC elongation and alignment. Both of these responses are partially recovered by the addition of heparin. ECs that overexpress TMEM184A have enhanced VE‐cadherin expression at adherens junctions after acclimation to laminar FSS. Treatment of ECs with VEGF to stimulate VEGFR2 produces substantial changes in TMEM184A dynamics and internalization under FSS conditions. Together, these data support a role for TMEM184A in mediating EC responses to laminar flow. Further research is necessary to confirm this role for the heparin receptor in order to assess potential applications for the treatment of cardiovascular disease.Support or Funding InformationNIH HL54269This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.