Myoendothelial junction heterogeneity and pathways of vasodilation
Ruddiman, Claire, Pharmacology - School of Medicine, University of Virginia
Isakson, Brant, MD-MPHY Mole Phys & Biophysics, University of Virginia
Myoendothelial junctions (MEJ) are key signaling microdomains in resistance arteries, the key component of the vasculature in regulating blood pressure. Anatomically, they are endothelial cell (EC) projections that connect with smooth muscle cells (SMC) in the arterial wall through projecting through holes in the internal elastic lamina (HIEL), the extracellular matrix that separates the two cell types. Specific protein localization to the MEJ coordinates vasodilation in resistance arteries through endothelial derived hyperpolarization (EDH). In Chapter 2, I describe the structural and functional consequences of inducing MEJ formation in a conduit artery, which results in a shift from nitric oxide (NO) to EDH based signaling. In Chapter 3, I (1) provide evidence that every HIEL contains an MEJ, (2) demonstrate that MEJs are randomly distributed in endothelium, (3) implicate lipid localization as a determinant for MEJ heterogeneity, (4) propose a function for PS localization at a subpopulation of MEJs, and (5) introduce a mouse model for disrupting MEJ signaling. In Chapter 4, I (1) show that a mouse model with elastin deleted from ECs disrupts IEL morphology in resistance arteries, (2) vasodilation shifts from EDH to NO based signaling, and (3) SMC function is affected by EC elastin deposition. In Chapter 5, I investigate the molecular composition of the IEL in resistance arteries and speculate how this may contribute to HIEL stability. In Chapter 6, I report on an effort to create a custom antibody to identify vascular connexins. Altogether, my data converges on the following key ideas: (1) MEJs are stable structures with heterogenous protein composition that is determined by local lipid composition, (2) the anatomical MEJ coordinates protein expression and localization to form functional microdomains, and (3) EC-derived elastin deposition coordinates MEJ formation and signaling within the resistance arterial wall.
PHD (Doctor of Philosophy)
endothelial cell, artery, cardiovascular, myoendothelial junction, internal elastic lamina, smooth muscle cell, vasodilation, elastin, microcirculation, resistance arteries, blood pressure, spatial distribution, matlab, nitric oxide, endothelial derived hyperpolarization, phosphatidylserine, lipids, ion channel
National Heart, Lung, and Blood Institute