Microvascular inflammation and dysfunction is widely believed to be the underlying cause of many of the clinical complications of diabetes and metabolic disease including renal and heart failure, neuropathy, and maculae degeneration. Much is known regarding mechanisms by which leucocytes and endothelial cells (EC) contribute to this process. However, in spite of compelling evidence that abnormal investment of perivascular smooth muscle cells and pericytes (SMC-Pc) is a common feature of microvascular disease pathogenesis, little is known regarding the role or mechanisms by which these cells might contribute to this process. Inadequate SMC-Pc investment of nascent EC tubes is also a major rate-limiting factor in attempts to induce therapeutic angiogenesis to augment wound repair or recovery from ischemic injury. Indeed, this includes many failed VEGF clinical trials where there is robust formation of EC tubes but failure to form a mature functional vascular network with efficient blood delivery because vessels lack SMC-Pc coverage and are dilated and leaky. Studies in this proposal will test the overall hypothesis that the stem cell pluripotency genes Oct4 and Klf4 play a critical role in regulating the plasticity of microvascular SMC-Pc during vascular remodeling in response to injury and hypoxia, as well as development of microvascular inflammation and dysfunction associated with metabolic disease. Consistent with this hypothesis, initial studies by our lab using unique SMC-Pc specific eYFP lineage tracing mice +/- simultaneous conditional knockout (KO) of Oct4 exclusively in SMC-Pc showed that Oct4 expression within SMC-Pc is required for functional angiogenesis in corneal burn and hind limb ischemia models. Moreover, we present exciting new data in this revised application showing that Klf4 expression within microvascular SMC-Pc plays a critical role in regulating the innate metabolic and inflammatory properties of the mesenteric microvascular network and surrounding adipose tissue even in non-hyperlipidemic mice.
Aim 1 will test the hypothesis that activation of Oct4 within microvascular SMC-Pc is a key rate-limiting step in both normal and dysfunctional angiogenesis including that associated with diet-induced obesity (DIO)/metabolic disease.
Aim 2 will determine mechanisms that regulate Oct4 re-activation within microvascular SMC-Pc including testing the hypothesis that it is hypoxia, NF?B, and Klf4-dependent.
Aim 3 will test the hypothesis that Klf4-dependent phenotypic transitions of microvascular SMC-Pc play a key protective role in regulating the innate metabolic and inflammatory properties of normal adipose tissue and that loss of these protective effects contribute to global microvascular inflammation/dysfunction during development of metabolic disease. Studies may lead to novel therapeutic approaches for enhancing therapeutic angiogenesis and/or treating and preventing microvascular disease complications of diabetes and metabolic disease.
/Relevance: Microvascular inflammation and dysfunction is widely believed to be the underlying cause of most of the long term clinical complications of diabetes and metabolic disease including renal and heart failure, neuropathy, atherosclerosis, stroke, and maculae degeneration which is the leading cause of blindness. Whereas there have been extensive studies of the role of endothelial cells and leucocytes in this process, very little is known regarding the role of the perivascular cells, including smooth muscle cells, and pericytes (SMC-Pc) that make up the walls of blood vessels and which are required for blood vessel maturation and formation of functional vascular networks that are effective in providing efficient blood delivery to tissues (a process we refer to as ?functional angiogenesis?). Studies in this proposal will define fundamental mechanisms that normally regulate SMC-Pc investment and maturation of small blood vessels during wound repair or responses to reduced oxygen supply, as well as how these processes are dysregulated as a major part of the pathogenesis of metabolic disease and diabetes which are increasing at a frightening rate due to the worldwide obesity epidemic. The knowledge gained in our studies may lead to novel therapeutic approaches for treating or preventing microvascular disease complications of diabetes and metabolic disease, and/or ways to promote improved vascularization of diseased or damaged tissues.
| Baylis, Richard A; Gomez, Delphine; Mallat, Ziad et al. (2017) The CANTOS Trial: One Important Step for Clinical Cardiology but a Giant Leap for Vascular Biology. Arterioscler Thromb Vasc Biol 37:e174-e177 |
| Murgai, Meera; Ju, Wei; Eason, Matthew et al. (2017) KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat Med 23:1176-1190 |
