The objectives of this proposal are to determine exactly how small collateral arteries and the microcirculation adapt to the chronic impairment of arterial inflow and to evaluate potential mechanisms that may mediate the acute and chronic vascular responses. For this purpose, I have developed a chronic technique that makes it possible to repeatedly observe the exact same vessels over a period of weeks to months. The entire intestinal vasculature from the arteries in the mesentery to the arterioles and capillaries of the submucosa and muscle layers can be studied. Pilot studies have demonstrated that the severity of the arterial inflow problem can be varied by the number of arteries ligated and that adult rats can permanently tolerate up to a 50% reduction in tissue blood flow. I have found that dilation of the small arteries and arterioles occurs immediately after arterial occlusion and that within one week there is selective enlargement of those collateral arteries and arterioles, which by their anatomical location, must experience increased blood flow. Similar vessels at the center of the collateral dependent region are not chronically enlarged. Microvascular pressure measurements and calculations of resistance indicate that microvascular pressures are restored to near normal in about 1 week by decreased resistance through these chronically enlarged collateral arteries and arterioles. I will evaluate the roles of flow-dependent, EDRF-mediated vasodilation and oxygen-dependent metabolic control in the vascular responses and test for the propagation of vasodilation by cell-to-cell communication from one vascular segment to the next. As the nature and course of compensation may evolve over time, the vascular responses will be studied immediately after sudden arterial occlusion and at early and late time points in the adaptive process. I will also use different degrees of arterial inflow restriction to determine how the severity of the initial insult influences the mechanisms involved and the major site and format of the compensation. Additional insight into the mechanisms involved will be obtained by selective placement of the arterial ligatures so that, in some cases, the majority of collateral flow occurs through small arteries located a considerable distance from the dependent tissue and, in other cases, through arterioles immediately adjacent to the dependent tissue. The effect of the chronic adaptation of vessels on passive distensibility and vascular reactivity will also be evaluated in collateral arteries and arterioles that are exposed to chronically increased blood flow and in similar types of vessels in the center of the collateral dependent tissue where blood flow and/or pressure may be chronically depressed. These studies will be the first to evaluate the same set of macro- and microscope vessels before occlusion and through various stages of compensation following the onset of arterial occlusion. The results will provide definitive information regarding the underlying mechanisms which initiate either compensatory or pathological responses to arterial restrictive disease and identify exactly what vessels are involved.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL042898-04
Application #
2220738
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1991-08-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ziegler, Matthew A; DiStasi, Matthew R; Miller, Steven J et al. (2016) Novel method to assess arterial insufficiency in rodent hind limb. J Surg Res 201:170-80
Miller, Steven J; Coppinger, Brian J; Zhou, Xiaosun et al. (2010) Antioxidants reverse age-related collateral growth impairment. J Vasc Res 47:108-14
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
Distasi, Matthew R; Case, Jamie; Ziegler, Matthew A et al. (2009) Suppressed hindlimb perfusion in Rac2-/- and Nox2-/- mice does not result from impaired collateral growth. Am J Physiol Heart Circ Physiol 296:H877-86
Zhou, Xiaosun; Bohlen, H Glenn; Unthank, Joseph L et al. (2009) Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide. Am J Physiol Heart Circ Physiol 297:H2227-33
Bohlen, H G; Zhou, X; Unthank, J L et al. (2009) Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation. Am J Physiol Heart Circ Physiol 297:H1337-46