Interactions between vascular integrins and ECM components of the blood vessel wall are important determinants of arteriolar tone and blood flow control. In Project 2, we focus on two aspects of vascular function in which ECM-integrin interactions acutely regulate vascular tone: 1) mechanotransduction of intravascular pressure through voltage-gated, L-type Ca^* channels (CBL) and BK (large-conductance calcium-activated K*) channels, and 2) the effects of biologically active matricryptins (i.e., proteolytic fragments of ECM proteins with vasoactive properties). The central hvpothesis of Project 2 is that a5B1 inteqrin plavs a critical role in mediatinq the transduction of physiological stretch to mVSM ion channels to enhance mvoqenic tone, while avB3 inteqrin functions as a matricryptin receptor to inhibit myoqenic tone and initiate vasodilation in response to vessel wall iniurv. The hypothesis will be tested using patch-clamp methods to record CaL and BK (large-conductance calcium-activated K* channel) currents in single rat or mouse mVSM cells and diameter responses of isolated arterioles in conjunction with adenoviral methods to manipulate the expression of selected proteins in arteriolar smooth muscle. There are two specific aims Aim A will focus on how longitudinal cell stretch is transduced through integrins to potentiate CBL and BK channels and myogenic tone. We predict that: aSpi integrin but not avp3 integrin transduces mechanical force to regulate CBL and BK channels;talin-1, paxillin, a-actinin and p130Cas are critical focal adhesion proteins required for force transmission through integrins to VSM channels;stretch-induced potentiation of by integrin-linked kinases and phosphatases.
Aim B will focus on how avpS integrin functions as a matricryptin receptor to inhibit myogenic tone. We predict that: fibronectin, osteopontin and collagen contain matricryptic sites that induce arteriolar dilatation;matricryptins act by inhibition of mVSM CaL channels and/or activation of BK channels;matricryptin-induced signaling through avpS integrin is mediated by phosphorylation of the p3 integrin tail by Src. The studies will expand our knowledge of how physiologic stretch regulates key VSM ion channels and how proteolytic fragments of ECM proteins exert their vasoactive effects.

Public Health Relevance

These studies are relevant to our understanding control of tissue blood flow and blood pressure by proteins that govern cell attachment in the blood vessel wall. Studies focus on how unique proteins regulate movement of ion across cell membranes. This information will expand our knowledge ofthe causes of vascular disease provide insights for new therapeutic strategies to regulate blood vessel diameter.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095486-05
Application #
8628157
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$364,994
Indirect Cost
$121,457
Name
University of Missouri-Columbia
Department
Type
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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