Cardiovascular disease (CVD), which includes arterial occlusive disease (AOD), is the primary cause of mortality and morbidity in the United States. Aging is a major risk factor for CVD, thus a rapidly increasing aged population will result in markedly increased incidences of all types of occlusive vascular diseases. The normal compensatory response to an arterial occlusion is the enlargement of preexisting collateral arteries that bypass the site of occlusion, but this process is severely impaired with aging. The mechanisms responsible for the age-related impairment in collateral enlargement are unknown, and determination of these mechanisms is a current and long-term goal of this project. Preliminary data from our laboratory demonstrate that aging incurs a decrease in available nitric oxide (NO) essential for collateral growth, and that inhibition of NAD(P)H oxidase reverses both the age-related impairment in flow-dependent production of NO and collateral growth. The central hypothesis of this proposal is that the age-related impairment in collateral growth is due to reduced levels of bioavailable NO in response to elevated flow resulting from dysregulation of the endothelial NO and NAD(P)H oxidase systems.
Three specific aims will examine mechanisms that regulate NO bioavailability during successful collateral growth and its impairment with aging: 1) Measure age-related changes in bioavailable NO during distinct phases of collateral development. 2) Determine the extent to which molecules that govern NO bioavailability are dysregulated during vascular aging in the distinct phases of collateral development. 3) Determine the effectiveness of alternative anti- oxidant treatments to reverse the age-related impairment of NO-dependent collateral growth. Periarterial NO in young and old rats will be measured under conditions of acute and chronic increases in flow with microelectrodes. Antioxidants and NO cofactors and substrates will be used to determine the pathways involved in regulation of bioavailable NO. Protein and metabolite expression analysis with immunoblotting and HPLC will be used to identify molecules that regulate NO and reactive oxygen species (ROS) during aging. It is our expectation that the successful completion of the proposed aims will show that a disrupted redox balance between NO and ROS contributes to a decrease in NO bioavailability and thus a reduction in the extent of collateral growth during aging. These findings would be significant because they would identify potentially important metabolic pathways and molecules that become abnormally regulated during aging. This is especially relevant to treating AOD in light of the failure of current experimental therapies, such as growth factors, to treat peripheral vascular disease. It is likely that approaches to increase NO bioavailability will be successful alone and also enhance growth factor- and cell-based therapies for promoting collateral artery growth in the rapidly increasing human population at risk for vascular occlusive diseases.

Public Health Relevance

The normal response to an arterial occlusion is the enlargement of preexisting collateral pathways that bypass the site of occlusion. However, this response is impaired with aging due to decreased availability of nitric oxide. The objective of this project is to identify mechanisms by which the flow-mediated production of nitric oxide is inhibited in collateral arteries of aging animals.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Thrasher, Terry N
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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DiStasi, Matthew R; Mund, Julie A; Bohlen, H Glenn et al. (2015) Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox. Am J Physiol Heart Circ Physiol 309:H1207-17
DiStasi, Matthew R; Unthank, Joseph L; Miller, Steven J (2014) Nox2 and p47(phox) modulate compensatory growth of primary collateral arteries. Am J Physiol Heart Circ Physiol 306:H1435-43
Ziegler, Matthew A; Distasi, Matthew R; Bills, Randall G et al. (2010) Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion. Microcirculation 17:3-20