Extracellular ATP: potential regulator of hypoxia-induced vasa vasorum neovascula

Summary

Principal Investigator: Evgenia Gerasimovskaya
Affiliation: University of Colorado Denver
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2008-07-10 - 2013-06-30
more information: NIH RePORT

Top Publications

  1. pmc Chronic hypoxia impairs extracellular nucleotide metabolism and barrier function in pulmonary artery vasa vasorum endothelial cells
    Gennady G Yegutkin
    MediCity Research Laboratory, University of Turku and National Institute of Health and Welfare, Tykistokatu 6A, 20520, Turku, Finland
    Angiogenesis 14:503-13. 2011
  2. pmc Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension
    Adil Anwar
    Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 303:L1-L11. 2012
  3. pmc The adventitia: essential regulator of vascular wall structure and function
    Kurt R Stenmark
    Division of Pediatric Critical Care, University of Colorado Denver, Aurora, Colorado 80045, USA
    Annu Rev Physiol 75:23-47. 2013
  4. pmc High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization
    Hala Nijmeh
    Univ of Colorado Denver, Pediatric Critical Care Medicine, Box B131, Research 2, Rm 6119, 12700 E 19th Ave, Aurora, CO 80045
    Am J Physiol Lung Cell Mol Physiol 306:L661-71. 2014
  5. pmc P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells
    Taras Lyubchenko
    Dept of Pediatrics, University of Colorado Denver, Research 2, Box B131, Aurora, CO 80045, USA
    Am J Physiol Cell Physiol 300:C266-75. 2011
  6. pmc Complementary effects of extracellular nucleotides and platelet-derived extracts on angiogenesis of vasa vasorum endothelial cells in vitro and subcutaneous Matrigel plugs in vivo
    Mark Roedersheimer
    Department of Pediatrics, University of Colorado Denver, 12700 East 19th Ave, Aurora, CO 80045, USA
    Vasc Cell 3:4. 2011
  7. pmc Interplay of macrophages and T cells in the lung vasculature
    Evgenia Gerasimovskaya
    Department of Pediatrics, University of Colorado Denver, 12700 E 19th Ave, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1014-22. 2012
  8. pmc 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
    Heather N Woodward
    Department of Pediatrics, 12700 E 19th Ave, University of Colorado Denver, Research Complex 2, Box B131, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 297:L954-64. 2009

Scientific Experts

  • Evgenia Gerasimovskaya
  • Kurt R Stenmark
  • Hala Nijmeh
  • Nana Burns
  • Adil Anwar
  • Maria G Frid
  • Min Li
  • Suzette R Riddle
  • Gennady G Yegutkin
  • Taras Lyubchenko
  • Mark Roedersheimer
  • Heather N Woodward
  • Aftab Ahmad
  • Vivek Balasubramaniam
  • Karim C El Kasmi
  • Eva Nozik-Grayck
  • Michael E Yeager
  • Binod Kumar
  • Barbara O Meyrick
  • B Alexandre McKeon
  • Mehdi A Fini
  • Roopa Thukaram
  • Elzbieta Kaczmarek
  • Heather Woodward
  • Kristopher D Veo
  • Sirpa Jalkanen
  • Mikko Helenius
  • Asya A Sidiakova
  • Ganna A Liubchenko
  • Kurt Stenmark
  • Laimute Taraseviciene-Stewart
  • Suzette Riddle
  • Miguel Fragoso

Detail Information

Publications8

  1. pmc Chronic hypoxia impairs extracellular nucleotide metabolism and barrier function in pulmonary artery vasa vasorum endothelial cells
    Gennady G Yegutkin
    MediCity Research Laboratory, University of Turku and National Institute of Health and Welfare, Tykistokatu 6A, 20520, Turku, Finland
    Angiogenesis 14:503-13. 2011
    ....
  2. pmc Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension
    Adil Anwar
    Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 303:L1-L11. 2012
    ..Thus our data suggest OPN as an essential contributor to the activated (highly proliferative, migratory, and proinvasive) phenotype of pulmonary adventitial fibroblasts in hypoxic PH...
  3. pmc The adventitia: essential regulator of vascular wall structure and function
    Kurt R Stenmark
    Division of Pediatric Critical Care, University of Colorado Denver, Aurora, Colorado 80045, USA
    Annu Rev Physiol 75:23-47. 2013
    ..This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in...
  4. pmc High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization
    Hala Nijmeh
    Univ of Colorado Denver, Pediatric Critical Care Medicine, Box B131, Research 2, Rm 6119, 12700 E 19th Ave, Aurora, CO 80045
    Am J Physiol Lung Cell Mol Physiol 306:L661-71. 2014
    ..These cells may serve as a potential target for regulating VVEC neovascularization. ..
  5. pmc P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells
    Taras Lyubchenko
    Dept of Pediatrics, University of Colorado Denver, Research 2, Box B131, Aurora, CO 80045, USA
    Am J Physiol Cell Physiol 300:C266-75. 2011
    ....
  6. pmc Complementary effects of extracellular nucleotides and platelet-derived extracts on angiogenesis of vasa vasorum endothelial cells in vitro and subcutaneous Matrigel plugs in vivo
    Mark Roedersheimer
    Department of Pediatrics, University of Colorado Denver, 12700 East 19th Ave, Aurora, CO 80045, USA
    Vasc Cell 3:4. 2011
    ..abstract:..
  7. pmc Interplay of macrophages and T cells in the lung vasculature
    Evgenia Gerasimovskaya
    Department of Pediatrics, University of Colorado Denver, 12700 E 19th Ave, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1014-22. 2012
    ..No labeled RAW 264.7 cells were detected in the lungs of immune-competent SD rats. Our data demonstrate that T cells can inhibit in vitro migration and in vivo accumulation of macrophage-like cells...
  8. pmc 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
    Heather N Woodward
    Department of Pediatrics, 12700 E 19th Ave, University of Colorado Denver, Research Complex 2, Box B131, Aurora, CO 80045, USA
    Am J Physiol Lung Cell Mol Physiol 297:L954-64. 2009
    ..Taken together, our findings provide novel evidence for the signaling mechanisms that link hypoxia-induced increases in extracellular ATP and vasa vasorum expansion...