The long-term goal of this project is to develop novel endothelium-targeted therapies for the prevention and treatment of cardiovascular disease. Discovery of circulating endothelial progenitor cells (EPCs) revolutionized understanding of the mechanisms responsible for endothelial repair after vascular injury and revascularization of ischemic tissues. However, the mechanisms underlying beneficial effects of EPCs are poorly understood. Prostacyclin (PGI2) is one of the most important vasoprotective molecules released from vascular endothelium. Strikingly, the role of arachidonic acid metabolism and biosynthesis of PGI2 in regulation of regenerative function of EPCs has not been studied. In our preliminary studies we identified intrinsically high biosynthesis of PGI2 as one of the major phenotypic characteristics of human EPCs. Furthermore, our studies indicate that pharmacological or genetic inactivation of PGI2 significantly impairs regenerative capacity of EPCs. Therefore, the general hypothesis of this application is that in the cardiovascular system, biosynthesis of PGI2 in EPCs is an essential mechanism responsible for the regenerative function of EPCs. To test this hypothesis we propose studies with the following specific aims: 1) determine expression and function of cyclooxygenase (COX) isoforms and profile of prostanoids biosynthesis in human EPCs, 2) define the role of PGI2 in regenerative functions of EPCs, and 3) analyze the role of arachidonic acid metabolism in aging-induced decline in regenerative capacity of EPCs. Experiments will be performed on EPCs isolated from circulating blood of healthy young and aged volunteers. The role of EPCs-derived PGI2 in repair injured endothelium or angiogenesis will be studied in vitro and in vivo. Established models of wire-induced injury of common carotid artery and hind limb ischemia in nude mice will be employed to determine the role of PGI2 derived from EPCs in endothelial repair and revascularization. Genetic modification of human EPCs will be carried out to gain further mechanistic insight into the role of arachidonic acid metabolism in reparative functions and aging of EPCs. The proposed studies will provide currently missing information regarding the role of prostanoids released from EPCs in response of the cardiovascular system to injury and aging. Understanding of these mechanisms will establish basis for development of novel therapeutic approaches to prevention and treatment of cardiovascular diseases.

Public Health Relevance

Project Narrative Endothelial Progenitor Cells (EPCs) are released from the bone marrow during cardiovascular diseases including myocardial infarction and stroke. Their major function is to repair injured blood vessels and restore normal cardiovascular function. Currently, efforts of many laboratories, including ours, are focused on understanding the mechanisms responsible for regenerative function of EPCs. The long-term goal of this application is to harness therapeutic potential of EPCs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
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Mayo Clinic, Rochester
United States
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d?Uscio, Livius V; Santhanam, Anantha V R; Katusic, Zvonimir S (2014) Erythropoietin prevents endothelial dysfunction in GTP-cyclohydrolase I-deficient hph1 mice. J Cardiovasc Pharmacol 64:514-21
d'Uscio, Livius V; He, Tongrong; Santhanam, Anantha Vijay R et al. (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene. Am J Physiol Heart Circ Physiol 306:H1001-10
Santhanam, Anantha Vijay R; d'Uscio, Livius V; Katusic, Zvonimir S (2014) Erythropoietin increases bioavailability of tetrahydrobiopterin and protects cerebral microvasculature against oxidative stress induced by eNOS uncoupling. J Neurochem 131:521-9
Katusic, Zvonimir S; Austin, Susan A (2014) Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35:888-94
Austin, Susan A; Santhanam, Anantha V; Hinton, David J et al. (2013) Endothelial nitric oxide deficiency promotes Alzheimer's disease pathology. J Neurochem 127:691-700
Austin, Susan A; d'Uscio, Livius V; Katusic, Zvonimir S (2013) Supplementation of nitric oxide attenuates AýýPP and BACE1 protein in cerebral microcirculation of eNOS-deficient mice. J Alzheimers Dis 33:29-33
He, Tongrong; Katusic, Zvonimir S (2012) Brain-derived neurotrophic factor increases expression of MnSOD in human circulating angiogenic cells. Microvasc Res 83:366-71
Nath, Karl A; Katusic, Zvonimir S (2012) Vasculature and kidney complications in sickle cell disease. J Am Soc Nephrol 23:781-4
d'Uscio, Livius V; Smith, Leslie A; Katusic, Zvonimir S (2011) Differential effects of eNOS uncoupling on conduit and small arteries in GTP-cyclohydrolase I-deficient hph-1 mice. Am J Physiol Heart Circ Physiol 301:H2227-34
He, Tongrong; Smith, Leslie A; Lu, Tong et al. (2011) Activation of peroxisome proliferator-activated receptor-{delta} enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin. Hypertension 58:287-94

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