This is a proposal to investigate the effects of cardiac compression on the vasoactive function of the endothelium of coronary arterioles and the mechanisms underlying the endothelial deformation-induced release of NO. The endothelium of intramural coronary arterioles is constantly exposed to rhythmic compression induced by cardiac contraction, which may affect its function. My hypothesis is that endothelial cells of coronary arterioles are sensitive to cellular deformation and in response release NO to restore their original shape by dilating the vessels. This hypothesis will be tested in rats at three subsequent levels: perfused hearts, isolated coronary arterioles and cultured endothelial cells of coronary arterioles.
In Specific Aim 1 in isolated and perfused heart, I aim to examine the relationship between the frequency and magnitude of cardiac compression and coronary flow. I will examine the role of NO in cardiac compression-induced increases in coronary flow and contrast the results with those obtained by flow- or myogenically-induced increases in flow.
In Specific Aim 2, I plan to study the effects of vascular compression on the diameter of isolated coronary arterioles, on the release of NO, and on the myogenic response and flow-induced dilation.
In Specific Aim 3, in cultured endothelial cells, I aim to monitor the changes in [Ca2+]I and the release of NO in response to endothelial deformation induced by compression, and to elucidate the correlation between [Ca2+]I and the increases in Cytosolic NO. Finally, in Specific Aim 4, I plan to investigate the possible signal transduction pathways involved in endothelial deformation-induced release of NO. The specific role of endothelial potassium channels, cytoskeleton and caveolae will be studied. I believe that the findings revealed by these studies will demonstrate a new physiologic control mechanism, namely, that cardiac contractions, by reducing arteriolar diameter and hence changing the shape of endothelial cells enhance the release of NO, which then participates in the regulation of coronary blood flow.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068813-05
Application #
6979808
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Schwartz, Lisa
Project Start
2001-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$229,233
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Huang, An; Yan, Changdong; Suematsu, Nobuhiro et al. (2010) Impaired flow-induced dilation of coronary arterioles of dogs fed a low-salt diet: roles of ANG II, PKC, and NAD(P)H oxidase. Am J Physiol Heart Circ Physiol 299:H1476-83
Yang, Yang-Ming; Huang, An; Kaley, Gabor et al. (2009) eNOS uncoupling and endothelial dysfunction in aged vessels. Am J Physiol Heart Circ Physiol 297:H1829-36
Yan, Changdong; Huang, An; Kaley, Gabor et al. (2007) Chronic high blood flow potentiates shear stress-induced release of NO in arteries of aged rats. Am J Physiol Heart Circ Physiol 293:H3105-10
Jacobson, Azita; Yan, Changdong; Gao, Qun et al. (2007) Aging enhances pressure-induced arterial superoxide formation. Am J Physiol Heart Circ Physiol 293:H1344-50
Williams, Jeffrey G; Rincon-Skinner, Tibisay; Sun, Dong et al. (2007) Role of nitric oxide in the coupling of myocardial oxygen consumption and coronary vascular dynamics during pregnancy in the dog. Am J Physiol Heart Circ Physiol 293:H2479-86
Sun, Dong; Yan, Changdong; Jacobson, Azita et al. (2007) Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ERalpha knockout mice: role of aromatase. Am J Physiol Regul Integr Comp Physiol 293:R1239-46
Sun, Dong; Liu, Hong; Yan, Changdong et al. (2006) COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice. Am J Physiol Heart Circ Physiol 291:H1429-35
Huang, An; Sun, Dong; Jacobson, Azita et al. (2005) Epoxyeicosatrienoic acids are released to mediate shear stress-dependent hyperpolarization of arteriolar smooth muscle. Circ Res 96:376-83
Yan, Changdong; Huang, An; Wu, Zhiping et al. (2005) Increased superoxide leads to decreased flow-induced dilation in resistance arteries of Mn-SOD-deficient mice. Am J Physiol Heart Circ Physiol 288:H2225-31
Huang, An; Sun, Dong; Yan, Changdong et al. (2005) Contribution of 20-HETE to augmented myogenic constriction in coronary arteries of endothelial NO synthase knockout mice. Hypertension 46:607-13

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