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 arterioscleroti 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 Our published and unpublished preliminary data indicate that Wnt7b regulation of diabetic arteriosclerosis differs between EC, mesenchymal/smooth muscle and myeloid lineages.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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069229-17
Application #
9223722
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
2001-09-30
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
17
Fiscal Year
2017
Total Cost
$405,000
Indirect Cost
$155,000
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Crewe, Clair; Joffin, Nolwenn; Rutkowski, Joseph M et al. (2018) An Endothelial-to-Adipocyte Extracellular Vesicle Axis Governed by Metabolic State. Cell 175:695-708.e13
Ramachandran, Bindu; Stabley, John N; Cheng, Su-Li et al. (2018) A GTPase-activating protein-binding protein (G3BP1)/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells. J Biol Chem 293:7942-7968
Gay, Austin; Towler, Dwight A (2017) Wnt signaling in cardiovascular disease: opportunities and challenges. Curr Opin Lipidol 28:387-396
Towler, Dwight A (2017) ""Osteotropic"" Wnt/LRP Signals: High-Wire Artists in a Balancing Act Regulating Aortic Structure and Function. Arterioscler Thromb Vasc Biol 37:392-395
Towler, Dwight A (2017) Commonalities Between Vasculature and Bone: An Osseocentric View of Arteriosclerosis. Circulation 135:320-322
Stabley, John N; Towler, Dwight A (2017) Arterial Calcification in Diabetes Mellitus: Preclinical Models and Translational Implications. Arterioscler Thromb Vasc Biol 37:205-217
Towler, Dwight A (2017) Lipoprotein(a): A Taxi for Autotaxin Takes a Toll in Calcific Aortic Valve Disease. JACC Basic Transl Sci 2:241-243
Towler, Dwight A (2016) AMPK?1: SUMO Wrestling Runx2 as a Strategy to Inhibit Arteriosclerotic Calcification. Circ Res 119:398-400
Towler, Dwight A (2015) Arteriosclerotic Calcification: A Serpi(n)ginous Path to Cardiovascular Health? Circ Res 117:744-6
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

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