Toward Functional Revascularization: Regulation of Vascular Network Remodeling Through Altered Hemodynamics

Abstract

Specific Aims and Executive Summary:In ischemic tissues downstream of an arterial occlusion, capillaries grow from existing vessels via angiogenesis. In contrast, collateral arteries around the occlusion undergo structural lumenal expansion (arteriogenesis). While it is known that mechanical stimuli from altered hemodynamics and bone marrow-derived cells (BMCs) play different individual roles in angiogenesis (1) and arteriogenesis (2), how these elements interact to guide the remodeling of the peripheral vasculature to reperfuse the downstream ischemic tissue is largely unknown and intensely debated (see reviews (3-5)). Improper understanding of the balance of angiogenesis versus arteriogenesis and the distribution of stimuli during remodeling has been cited as the primary reason for the failure of numerous clinical trials targeting therapeutic revascularization efforts toward treating peripheral arterial disease (PAD) (4,6,7). These vascular remodeling elements are further interwoven with the endogenous capacity to tolerate ischemia and regenerate tissue for a full functional compensation to PAD. Given the prevalence (>20% of those >65 years of age (8)) and economic impact ($4.4 billion estimated treatment costs (9)) of PAD, there is a critical need to identify better targets for therapeutic intervention both in terms of the types of remodeling to promote and the molecular targets for accelerating the growth needed for a functional recovery.To meet this problem, the following research plan was used to address several key issues in the field that are needed to develop effective revascularization therapies. First, we proposed using two separate mouse models to determine, for the first time, how arteriogenesis, angiogenesis, and muscle regeneration quantitatively contribute to reperfusion after arterial occlusion in order to identify the relative importance of targeting each type of remodeling for revascularization therapies (Aim 1). Second, we developed and validated the use of quantitative laser speckle flowmetry (LSF) as a tool for determining how ii the distribution of hemodynamic changes guides arterial remodeling (Aim 2). Finally, preliminary data from our laboratory suggested that regional variation in pre-existing hemodynamic directionality determines the rate and capacity for arteriogenesis across a network. Using the novel tools developed to map hemodynamic change across a network at the arteriole level, we produced the first direct measurements of the changes in shear stress that drive the arteriogenic process. From these novel data, we demonstrated how differential mechanotransduction due to pre-existing endothelial polarity functions as an independent enhancer of arteriogenesis that can be used to identify critical pathways for enhancing collateral development (Aim 3).Aim 1: Determine the contribution of angiogenesis and skeletal muscle regeneration to reperfusion after arterial occlusion in the ischemic mouse hindlimb model. Hypothesis: Mouse models of femoral artery ligation (FAL) that exhibit speci...