Abstract

Hypertension is associated with structural changes to the resistance vasculature leading to a reduction in resistance artery diameter. This process is termed inward remodeling and is defined as a reduction in lumenal diameter under passive conditions. We posit that inward remodeling involves dynamic changes to the actin cytoskeleton that facilitate the movement and rearrangement of vascular smooth muscle cells around a smaller vascular lumen. Ex vivo, prolonged exposure to vasoconstrictors has been demonstrated to induce remodeling via g‐protein coupled receptors (GPCR) that activate the Rho signaling pathway and subsequently promote actin polymerization. We report here that vascular smooth muscle cells, propagated on nanopatterned culture‐ware to maintain their contractile phenotype, increase their ratio of filamentous (F) to globular (G)‐actin in response to GPCR activation by Norepinephrine and Angiotensin (Ang) II. One of the enzymes in the Rho signaling pathway implicated in the increase in F/G‐actin following GPCR activation is Lim Kinase, which phosphorylates and inactivates the actin severing enzyme, cofilin. In isolated rat cremasteric arteries we demonstrate that inhibition of Lim Kinase blocks inward remodeling in the presence of GPCR agonists and this is coincident with a reduction in cofilin phosphorylation. To examine the process in vivo, we utilized a transgenic mouse line that expresses smooth muscle actin (SMA)‐GFP in vascular smooth muscle cells to measure proximal arterial diameter noninvasively within the outer ears using confocal microscopy. Exposure of these mice to 1000 ng/kg/min of Ang II for two weeks resulted in a significant increase in mean arterial blood pressure. Both ears were imaged prior to Ang II infusion (Day 0) and after 14 days of infusion to assess inward remodeling. Starting at day 0, the right ear was injected with a bolus of a Lim Kinase inhibitor (10 uM) and the left ear was injected with vehicle. Injections were repeated every 4 days for a total of four injections. The vehicle exposed ears significantly inwardly remodeled in contrast to those exposed to the Lim Kinase inhibitor (Vehicle diameter = −15.95 % +/− 1.79 versus Lim Kinase inhibitor diameter = −1.75% +/− 1.78, P<0.05). These data demonstrate that in vivo, Lim Kinase plays a necessary role in inward remodeling, and thus merits additional study as a potential therapeutic target in cardiovascular pathologies associated with inward remodeling.Support or Funding InformationNIH‐HL‐088105 to LAMThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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