Vascular occlusive disease poses an increasing burden on healthcare systems. Blockage of major arteries causes severe ischemic damage to tissues, with the potential of limb loss, organ dysfunction, and death. As a response to occlusion, however, collateral vessels are able to remodel to bypass the occlusion, a process termed arteriogenesis. Accumulating evidence implicates myeloid cells as key mediators of this remodeling, however the exact role these cells play in arteriogenesis remains unclear. Previous studies from our group have identified KLF2 as a transcriptional regulator of myeloid cell activation, a process critical for effective arteriogenesis. Nascent observations in our lab demonstrate that loss of KLF2 in the myeloid compartment greatly enhances perfusion recovery following a model of hindlimb ischemia (HLI). In addition, these differences appear to be greatly dependent on induction of the prominent inflammatory enzyme, inducible nitric oxide synthase (iNOS). Modification of critical proteins in vascular cells by S-nitrosylation has been shown to greatly affect functions crucial to vascular remodeling. These findings provide the basis for our central hypothesis that KLF2 serves as a regulator of macrophage-mediated nitric oxide (NO) production that affects the S-nitrosoproteome of endothelial and smooth muscle cells during occlusive injury. The proposed study will vigorously interrogate the effects of myeloid-KLF2 on vascular remodeling. Specifically, we aim to examine whether KLF2 serves as a nodal regulator of myeloid function during arteriogenesis, in part through its regulation of NO production. To accomplish this goal, this study will utilize a wide range of biochemical, molecular, and pharmacological techniques, including, but not limited to: in vivo models of arteriogenesis, microCT imaging, pharmacological modulation of NO, and S-nitrosylation assays. Together, these studies will provide crucial insight on the cellular and molecular processes leading to proper arteriogenesis and will provide the foundation for interventions targeting vascular occlusion with the goal of reducing debilitating complications for patients.
Cardiovascular disease is a major contributor to morbidity and mortality worldwide, with extensive complications resulting from blockage of blood flow in particular. In response to this blockage, vessels undergo extensive remodeling in a process called arteriogenesis that is largely orchestrated by infiltrating immune cells. Currently, treatments targeting these cells in arteriogenesis are hampered by the fact that overactivation of these cells can lead to adverse outcomes. This study aims to improve our understanding of the role of immune cells in the response to vascular occlusion and identify targetable mechanisms by which these cells influence arteriogenesis, with the hope of significantly reducing complications due to vascular injury.
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