Factors Controlling Peripheral Vessel Development

University Of Missouri-Columbia, Columbia MO

Investigators

Linked publications, trials & patents

Abstract

Preclinical studies are uniform in demonstrating enlargement of small pre-existing collateral vessels in mice,[unreadable] rats and rabbits following acute-onset hindlimb ischemia. In the presence of competent endothelial function,[unreadable] improved collateral flow is sufficient to moderate hindlimb ischemia over the relatively short distances in these[unreadable] animals. The response in humans, however, is different. While significant increases in clinical indices of[unreadable] perfusion and exercise tolerance are uniformly observed in patients with intermittent claudication with[unreadable] prompting stimuli (e.g., daily walking), this cannot be ascribed to improved collateral blood flow in many of the[unreadable] clinical studies. Meaningful improvement in limb flow capacity requires extensive enlargement of these small[unreadable] collateral vessels, far greater than observed in small mammals, to compensate for the high conductance that[unreadable] normally supports flow to muscles at the long distances found in human legs. It is unknown whether the failure[unreadable] to observe significant increases in collateral blood flow in claudicant patients involved in exercise programs[unreadable] is due: 1) to an inability to develop sufficiently large collateral vessels due to an inadequate stimulus, or 2)[unreadable] to an inability to respond to an adequate stimulus that would normally prompt meaningful vessel enlargement.[unreadable] Further, it is unknown whether establishing a high arterial pressure (e.g., approximately 100 mmHg; increasing radial wall[unreadable] stress) within the large tortuous collateral conduits is sufficient to minimize regression of the vessel, in the[unreadable] absence of sustained arteriogenic stimuli that enlarged the collateral in the first place. Using a large mammal[unreadable] with femoral artery occlusion, we will: a) provide a commanding stimulus for collateral enlargement by[unreadable] increasing shear stress, using a unique arterial-venous shunt, and evaluate the competency of the[unreadable] endothelium to support collateral enlargement after inducing endothelial dysfunction by feeding the pigs an[unreadable] atherogenic diet, known to 'dull' endothelial responsiveness; b) assess the ability of exercise training to[unreadable] reverse the documented consequences of the HFC diet; and c) determine whether establishing a high luminal[unreadable] pressure is sufficient to retain large collateral vessels, once formed, in normal, atherogenic diet-fed, and[unreadable] exercise trained pigs. Instrumented limb blood flow (iliac a.), collateral network images, collateral blood flow[unreadable] (uspheres), in vitro function and morphology of collateral vessels, involvement of circulating vascular[unreadable] precursor cells, and functional capacity of the animals will be determined. Our evaluation of large-vessel[unreadable] collaterals should provide compelling evidence important in the management of claudicant patients with[unreadable] single-level, large-vessel proximal vascular lesions.