With advancing age, diabetes, impaired renal function, and hypertension, conduit arteries become increasingly arteriosclerotic, losing compliance necessary for smooth distal tissue perfusion. Arteriosclerotic calcification and fibrosis has emerged as an important contributor to cardiovascular morbidity and mortality in patients with type II diabetes (T2D). A better understanding of pathways that control arterial calcification, fibrosis, and compliance will lead to new strategies for diminishing arteriosclerotic disease burden. We identify Wnt7b as an important regulator of vascular calcification and tissue fibrosis - acting down-stream of and in concert with TNF and Msx2. Multiple vascular cell types express Wnt7b, including endothelial cells (ECs), subsets of monocyte/macrophages (myeloid lineage), and adventitial myofibroblasts (vascular smooth muscle lineage). In the prior funding cycle, studies of Msx deficiency (a) confirmed the role for Msx genes in vascular calcification;(b) suggested that neuropeptide Y (NPY) with TNF supports expression of vascular Wnt7b and Msx2: and (c) indicate that EC Wnt7b limits broader Wnt7b expression by other vascular cell types and thus osteofibrogenic vascular disease. Therefore, the specific Aims of this proposal are:
Aim1 : "To determine the contributions of vascular smooth muscle lineage (myofibroblast) vs. myeloid lineage Wnt7b expression to the pathobiology of diabetic arteriosclerosis, using SM22- Cre;Wnt7b(flox/flox);LDLR-/- and LysM-Cre;Wnt7b(flox/flox);LDLR-/- mice as models for study." Our published and unpublished preliminary data indicate that Wnt7b regulation of diabetic arteriosclerosis differs between EC, mesenchymal/smooth muscle and myeloid lineages.
This aim directly assesses the pro-sclerotic roles of Wnt7b in each lineage.
Aim 2 : "To characterize the role for neuropeptide Y / NPY1 receptor (NPY1R) signaling cascades in vascular Wnt7b expression and the osteogenic regulation of vascular calcification, using NPY1R-/-;LDLR-/- mice as a model for study." We recently identified NPY Y1R activity as participating in the pro-sclerotic actions of Msx genes and vascular Wnt7b expression. In this aim we genetically confirm this notion.
Sub aims (a) determine the vascular cell types expressing NPY and Wnt7b in diabetic arteriosclerosis;and (b) identify regulatory elements and signaling cascades supporting vascular myofibroblast Wnt7b genomic responses to NPY vs. TNF. The outcomes of these aims will provide physiological rationale and validation for targeting Wnt7b and NPY Y1R signaling as a potential therapeutic strategy to ameliorate arteriosclerotic calcification in diabetic vascular disease.
Arterial hardening in diabetes increases the risk for heart attacks, heart failure, stroke, and foot amputation. This occurs in part via metabolic &inflammatory signals that induce bone-like calcification in large arteries. We have identified that two proteins, Wnt7b and neuropeptide Y, are activated with calcification, fibrosis, and hardening of the arteries in diabetic mice. We test whether regulation of these proteins reduces arterial hardening, decreases cardiac workload, and improves heart and vascular circulatory function diabetes.
|Towler, Dwight A (2016) AMPKÎ±1: SUMO Wrestling Runx2 as a Strategy to Inhibit Arteriosclerotic Calcification. Circ Res 119:398-400|
|Cheng, Su-Li; Ramachandran, Bindu; Behrmann, Abraham et al. (2015) Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. Circ Res 117:142-56|
|Towler, Dwight A (2015) Arteriosclerosis, bone biology, and calciotropic hormone signaling: learning the ABCs of disease in the bone-vascular axis. J Am Soc Nephrol 26:243-5|
|Towler, Dwight A (2015) Arteriosclerotic Calcification: A Serpi(n)ginous Path to Cardiovascular Health? Circ Res 117:744-6|
|Cheng, Su-Li; Behrmann, Abraham; Shao, Jian-Su et al. (2014) Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 63:4326-37|
|Towler, Dwight A (2014) The platelet: sensing shear and the endocrine regulation of cardiovascular sclerosis. Arterioscler Thromb Vasc Biol 34:1803-5|
|Towler, Dwight A (2013) Molecular and cellular aspects of calcific aortic valve disease. Circ Res 113:198-208|
|Towler, Dwight A (2013) Chronic kidney disease: the "perfect storm" of cardiometabolic risk illuminates genetic diathesis in cardiovascular disease. J Am Coll Cardiol 62:799-801|
|Cheng, Su-Li; Shao, Jian-Su; Behrmann, Abraham et al. (2013) Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells. Arterioscler Thromb Vasc Biol 33:1679-89|
|Towler, Dwight A (2013) Mitochondrial ROS deficiency and diabetic complications: AMP[K]-lifying the adaptation to hyperglycemia. J Clin Invest 123:4573-6|
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