Pathological vascular remodeling is a key component and frequently life-threatening consequence, of vascular diseases in both the systemic and pulmonary circulation. In a neonatal model of hypoxic pulmonary hypertension, we have demonstrated that hypoxia-induced pulmonary artery (PA) remodeling is associated with marked increases in the density of vasa vasorum network. The observed increases in vasa density suggests that neovascularization process may contribute to the progression of pulmonary vascular remodeling and hypertension. The long-term goal of our studies is to evaluate the precise cellular mechanisms and endogenous molecular factors that mediate vasa vasorum neovascularization in hypoxia-induced pulmonary vascular remodeling. Extracellular adenine nucleotides are increasingly recognized as important regulators of vascular functions. Since within the PA adventitial compartment, ATP can be released from a number of vascular and blood cells in response to hypoxia, it could be expected that in the hypoxic vessel microenvironment, extracellular ATP may be the signaling molecules involved in the hypoxia-induced PA adventitial neovascularization. Our preliminary studies in vitro have demonstrated that vasa vasorum endothelial cells (VVEC) isolated from PA adventitia are distinct in their dramatic proliferative responses to extracellular ATP. In turn, hypoxia was found to be a potent inducer of ATP release. Therefore, we hypothesized that extracellular ATP may act as an autocrine/paracrine factor in stimulating hypoxia-induced angiogenic responses in VVEC. Using cultured vasa vasorum endothelial cell as a model system, the specific aims are proposed to (i) determine the angiogenic capacity of extracellular ATP and intracellular signaling pathways that play critical roles in hypoxia- and ATP-induced angiogenic responses in VVEC;(ii) elucidate the intracellular mechanisms through which hypoxia induces ATP release from VVEC;(iii) test the possibility that endogenously released ATP plays an autocrine role in mediating the effects of hypoxia in VVEC. Ultimately, this research proposal aspires to translate fundamental questions of purinergic signaling to the clinically relevant problem of hypoxia-induced angiogenesis. The characterization of an angiogenic phenotype of VVEC, including purinergic receptors and coupled signaling pathways, will provide unique targets for therapeutic strategies aimed at inhibiting pathologic angiogenesis in blood vessel wall.

Public Health Relevance

Pathological vascular remodeling is a key component and frequently life-threatening consequence of vascular diseases in both the systemic and pulmonary circulation. An increasing body of experimental data suggest that vasa vasorum expansion may contribute to hypoxia-induced pulmonary vascular remodeling associated with pulmonary arterial hypertension. Therefore, the long-term goal of our studies is to evaluate the precise cellular mechanisms and endogenous molecular factors that mediate vasa vasorum neovascularization. Specifically, using cultured vasa vasorum endothelial cells (VVEC) isolated from pulmonary adventitia of chronically hypoxic animals, we will test the hypothesis that extracellular ATP may act as an autocrine/paracrine factor in stimulating hypoxia-induced angiogenic responses in VVEC.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086783-05
Application #
8286912
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2008-07-10
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$378,675
Indirect Cost
$131,175
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Nijmeh, Hala; Balasubramaniam, Vivek; Burns, Nana et al. (2014) High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization. Am J Physiol Lung Cell Mol Physiol 306:L661-71
Stenmark, Kurt R; Yeager, Michael E; El Kasmi, Karim C et al. (2013) The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 75:23-47
Gerasimovskaya, Evgenia; Kratzer, Adelheid; Sidiakova, Asya et al. (2012) Interplay of macrophages and T cells in the lung vasculature. Am J Physiol Lung Cell Mol Physiol 302:L1014-22
Lyubchenko, Taras; Woodward, Heather; Veo, Kristopher D et al. (2011) P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells. Am J Physiol Cell Physiol 300:C266-75
Roedersheimer, Mark; Nijmeh, Hala; Burns, Nana et al. (2011) Complementary effects of extracellular nucleotides and platelet-derived extracts on angiogenesis of vasa vasorum endothelial cells in vitro and subcutaneous Matrigel plugs in vivo. Vasc Cell 3:4
Woodward, Heather N; Anwar, Adil; Riddle, Suzette et al. (2009) PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells. Am J Physiol Lung Cell Mol Physiol 297:L954-64