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 previously reported tha We have previously reported that similar to humans with IPAH, hypoxia-induced pulmonary artery (PA) remodeling is associated with marked increases in the density of vasa vasorum (VV) network, recruitment and infiltration of circulating progenitor and inflammatory cells to the PA, implicating VV in disease pathogenesis. The long-term goal of our studies is to evaluate 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. We demonstrated that the adventitial vasa vasorum endothelial cells (VVEC) are a potent source of extracellular ATP, which acts as an autocrine/paracrine factor mediating hypoxia-induced VVEC angiogenesis. Our data demonstrated that exaggerated nucleotide-mediated angiogenic responses in VVEC involve activation of P2Y1, and P2Y13 purinergic receptors, PI3K/Akt/mTOR, ERK1/2, and the elevation of cytoplasmic, nucleoplasmic, and mitochondrial Ca2+. In addition, our preliminary data for this proposal we demonstrated the presence of subsets of P2Y13R expressing highly proliferative potential colony forming cells (VVECFC) in VVEC cultures, which might be responsible for angiogenic VV expansion. As the importance of cellular energy metabolism has been postulated to link cellular metabolic state and functional responses, in this proposal we will test the hypothesis that purinergic regulation of VV angiogenesis involves the activation of mitogenic and bioenergetic pathways in VVEC and VVECFC, leading to metabolic reorgnization/reprogramming and phenotypical changes in these cells towards differentiated endothelial phenotype. The studies proposed in three specific aims will: (i) Characterize a hierarchy of colony-forming cells residing in VVEC;determine their phenotype, proliferative and angiogenic capabilities;(ii) examine purinergic receptor-mediated signaling pathway in clonogenic, angiogenic, and signaling responses in VVEC and VVECFC;(iii) determine bioenergetic organization of VVEC and VVECFC and determine whether extracellular nucleotides and hypoxia induce angiogenic and phenotypic responses in these cells via energy metabolism and mitochondrial regulation. Ultimately, this research proposal aspires to translate fundamental questions of purinergic signaling to the clinically relevant problem of hypoxia-induced angiogenesis. Understanding of fundamental biological mechanisms of metabolic and signaling regulation of VV expansion to a functional vascular network will facilitate development of the innovative treatments for pulmonary hypertension and a variety of vascular diseases that involve impaired angiogenesis and pathologic vascular remodeling.

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 cellular mechanisms and endogenous molecular factors that mediate vasa vasorum neovascularization. Using cultured vasa vasorum endothelial cells (VVEC) isolated from pulmonary adventitia of control and chronically hypoxic animals, we propose to evaluate a role of purinergic receptors in regulating angiogenic signaling parthways and cellular bioenergetics critical in hypoxia-induced vasa vasorum angiogenic expansion.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01HL086783-06A1
Application #
8696521
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
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