Microvascular Function and Remodeling Due to Chronic Changes Within the Skeletal Muscle Microenvironment

The skeletal muscle microcirculation is a key regulator of local blood distribution, vascular resistance and overall blood pressure (BP). Arterioles and capillaries are two important components of the microcirculation, which can undergo remodeling such as arteriogenesis, angiogenesis, or capillary rarefaction. Vascular remodeling requires the coordinated action of several factors within the microenvironment. These include: matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), vascular endothelial growth factor-A (VEGF-A) and thrombospondin-1 (TSP-1). The objective of this dissertation was to examine how alterations to the microenvironment impacted the appropriate microvascular remodeling responses to alterations in flow. The skeletal muscle microenvironment was altered through manipulation of TIMP1 expression or glucocorticoid (GC) levels. Furthermore, blood flow was altered via femoral artery (FA) ligation or prazosin treatment. This dissertation includes three primary hypotheses and corresponding findings to examine the importance of alterations to the microenvironment on microvascular remodeling. Firstly, the loss of TIMP1 would enhance both ischemia and flow-induced vascular remodeling by increasing MMP activity. Using TIMP1 deficient mice (Timp1-/-), we demonstrated that TIMP1 is integral for vascular network maturation. Additionally, TIMP1 is required for microvascular adaptations to alterations in flow. This was proven by the absence of arteriogenesis and/or angiogenesis in Timp1-/- mice in response to elevations in flow despite an increase in both VEGF-A and eNOS mRNA. Secondly, Corticosterone (CORT) treatment would inhibit endothelial mediated shear stress signaling and subsequently, the microvascular remodeling responses to prazosin administration. Lastly, CORT mediated hypertension and microcirculatory rarefaction would be prevented with 2 weeks of concurrent prazosin or Tempol (a ROS scavenger) administration. Endothelial cell responsiveness to shear stress was partially blunted by CORT pre-treatment. The lack of vascular remodeling (angiogenesis and arteriogenesis) and prevention of GC-mediated capillary rarefaction in CORT-prazosin animals supports this finding. The maintenance of vascular tone and skeletal muscle blood flow, more so then lowering circulating levels of ROS, was responsible for mitigating CORT-induced capillary rarefaction and hypertension. Taken together, these three studies demonstrate that perturbations of the microenvironment, due to the loss of TIMP1 or elevated GCs, results in impaired microvascular remodeling to alterations in flow. Furthermore, alterations to the skeletal muscle microcirculation can impact overall cardiovascular health.