Marvels, Mysteries, and Misconceptions of Vascular Compensation to Peripheral Artery Occlusion

Abstract

Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.

Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED

“…76,77 However, these last two examples are also prone to diabetes, another risk factor for peripheral atherosclerosis. While some rat studies have used arterial occlusion to model reduced blood flow to the penis, overt occlusion is rarely seen in peripheral artery disease, 76 where the resulting pathology is most likely caused by impaired vascular function and capacity rather than fixed lesion stenosis.…”

“…76,77 Even in the genetic variants that are prone to develop atherosclerosis, the atherosclerosis is more centrally distributed (in conduit arteries and aorta) and results in rats have generally failed to predict clinical success. 76,77 However, these last two examples are also prone to diabetes, another risk factor for peripheral atherosclerosis. While some rat studies have used arterial occlusion to model reduced blood flow to the penis, overt occlusion is rarely seen in peripheral artery disease, 76 where the resulting pathology is most likely caused by impaired vascular function and capacity rather than fixed lesion stenosis.…”

“…Similarly, normal rats are quite resistant to the development of atherosclerosis (because of the HDL-C effect) but can be induced to develop atherosclerosis in conduit arteries by feeding them large amounts of cholesterol in their diet and/or supplementing their diets with thiopropyluracil to create hypothyroidism. 76,77 There are genetic variants of atherosclerosis-prone rats including Fatty Zucker rats and Corpulent rats. 76,77 Even in the genetic variants that are prone to develop atherosclerosis, the atherosclerosis is more centrally distributed (in conduit arteries and aorta) and results in rats have generally failed to predict clinical success.…”

“…76,77 There are genetic variants of atherosclerosis-prone rats including Fatty Zucker rats and Corpulent rats. 76,77 Even in the genetic variants that are prone to develop atherosclerosis, the atherosclerosis is more centrally distributed (in conduit arteries and aorta) and results in rats have generally failed to predict clinical success. 76,77 However, these last two examples are also prone to diabetes, another risk factor for peripheral atherosclerosis.…”

Ischemic Ulcer Healing: Does Appropriate Flow Reconstruction Stand for All That We Need?

“…Another parallel and more common anatomical partition used in CLI literature roughly distinguishes the macrocirculatory rank (that embodies previous levels I-IV) from the microcirculatory level (equivalent to other levels V and VI) of limb perfusion [1,27,29,30,[103][104][105][106]. By bridging these two levels, the medium and small muscular arteries and adjacent arterioles contribute to a continuous pacing system of local tissular perfusion [103][104][105].…”