Growth and regression of vasculature in healthy and diabetic mice after hindlimb ischemia

Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA.
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.11). 05/2012; 303(1):R48-56. DOI: 10.1152/ajpregu.00002.2012
Source: PubMed


The formation of vascular networks during embryogenesis and early stages of development encompasses complex and tightly regulated growth of blood vessels, followed by maturation of some vessels, and spatially controlled disconnection and pruning of others. The adult vasculature, while more quiescent, is also capable of adapting to changing physiological conditions by remodeling blood vessels. Numerous studies have focused on understanding key factors that drive vessel growth in the adult in response to ischemic injury. However, little is known about the extent of vessel rarefaction and its potential contribution to the final outcome of vascular recovery. We addressed this topic by characterizing the endogenous phases of vascular repair in a mouse model of hindlimb ischemia. We showed that this process is biphasic. It encompasses an initial rapid phase of vessel growth, followed by a later phase of vessel rarefaction. In healthy mice, this process resulted in partial recovery of perfusion and completely restored the ability of mice to run voluntarily. Given that the ability to revascularize can be compromised by a cardiovascular risk factor such as diabetes, we also examined vascular repair in diabetic mice. We found that paradoxically both the initial growth and subsequent regression of collateral vessels were more pronounced in the setting of diabetes and resulted in impaired recovery of perfusion and impaired functional status. In conclusion, our findings demonstrate that the formation of functional collateral vessels in the hindlimb requires vessel growth and subsequent vessel rarefaction. In the setting of diabetes, the physiological defect was not in the initial formation of vessels but rather in the inability to sustain newly formed vessels.

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    • "Shear stress is known as the key factor regulating collateral remodeling; therefore, the presence of high shear stress in these aberrant collateral vessels drives them to continue to grow, leading to a thick neo- intima. There is no doubt that shear stress is the driving force for collateral vessel growth after arterial occlusion, but the development of collateral vessels can be strongly affected by multiple factors, such as diabetes and variants in genes [Chalothorn and Faber, 2010;Landazuri et al., 2012]. In a previous study, we addressed the importance of adventitial remodeling in the development of collateral vessels[Cai et al., 2003], suggesting an active remodeling in the adventitia ensures the outward growth of collateral vessels and allows the formation of larger collaterals. "
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