Ischemia/reperfusion (I/R) induces leukoeyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated vasodllatory responses (EDD) in upstream arterioles. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that l/R-induced venular LECA is causally linked to EDD in arterioles. However, the mechanisms coupling l/R-induced postcapillary venular LECA and EDD in upstream arterioles are unknown. Our overall hypothesis is that l/R-induced EDD in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes which exposes matricryptic sites in the extracellular matrix (ECM) that interact with the integrin avp3 to induce mast cell-dependent formation of angiotensin II (Ang II). Subsequent activation of NAD(P)H oxidase promotes eNOS uncoupling in the vascular wall and leads to the formation of oxidants which inactivate NO, resulting in arteriolar EDD.
Our Specific Aims are to determine:
Aim A) whether venular LECA play an obligatory role in the development of EDD in upstream arterioles;
Aim B) the contribution of leukocyte-derived proteases to the development of arteriolar EDD;
Aim C) the role of avp3 integrin in initiating chymase-dependent formafion of Ang II;
and Aim D) the role of Ang ll-dependent, NAD(P)H oxidase- and uncoupled eNOS-mediated oxidant production in arteriolar EDD. Intravital microscopic approaches will be used to examine arteriolar EDD, venular LECA, and mast cell responses to I/R. Arterioles will be isolated from non-ischemic intesfine and exposed to posfischemic lymph, as a means to examine interstitial signals that are generated by the proteolytic acfivity of extravasated leukocytes. A novel three-dimensional ECM model engrafted with isolated cannulated arterioles and seeded with mast cells in the presence and absence of neutrophils will also be used to to further explore our hypothesis. Isolated arterioles obtained from a number of gene knockout and transgenic animal models will be used to further explore the mechanisms of arteriolar EDD. Collectively, these aims address a novel mechanism to explain the profound disturbance in arteriolar vasoregulatory funcfion in postischemic tissues. Significance: This work will identify new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, and EDD in arterioles. Given the importance of the endothelium in regulating vascular tone, these fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.

Public Health Relevance

Reductions in the blood supply (ischemia) to the heart, brain, kidneys, or intestine are major causes of death and disability. As a result of ischemia, arterial blood vessels become dysfunctional and unable to regulate their diameter. The goal of this project is to identify the cells and molecular pathways involved in the pathogenesis of arterial dysfunction after ischemia for design of new therapeutic approaches for treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095486-03
Application #
8376463
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$362,155
Indirect Cost
$123,109
Name
University of Missouri-Columbia
Department
Type
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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