Vascular calcification is a frequent complication of vascular disease associated with increased morbidity and mortality. It is recognized to be an active process involving osteochondrogenic differentiation in multipotent cells. Previous reports have suggested that endothelial cells (ECs) contribute calcifying cells in congenital disorders with soft tissue calcification, triggered by abnormal bone morphogenetic protein (BMP) signaling. Matrix Gla protein (MGP) is an inhibitor of vascular calcification, and an antagonist to BMP2/4. MGP null mice show strong activation of vascular BMP signaling and extensive aortic calcification. Ins2-Akita/+ mice, a model of type 1 diabetes, exhibit similar findings due to induction of BMPs and BMP receptors. Preliminary data show that BMP activation causes stem cell characteristics to emerge in normal ECs. Indeed, EC lineage markers co- stain with osteogenic and pluripotent stem cell markers in MGP null aortas, and MGP-depletion in human aortic ECs in vitro causes the cells to undergo osteogenic differentiation in response to osteoinductive factors. In addition, Ins2-Akita/+ mice exhibit increased aortic expression of multiple pluripotency-associated markers. Thus, normal ECs may contribute osteoprogenitor cells to vascular calcification when subjected to increased BMP activity. The scientific purpose of this proposal is to define the role of the endothelium in vascular calcification in MGP deficiency and diabetes. We hypothesize that normal endothelium contributes multipotent cells to vascular calcification due to the capacity of abnormal BMP activity to induce stem cell characteristics and subsequent osteogenesis.
Specific Aim 1 will define multipotency and osteochondrogenic potential in ECs in the setting of MGP deficiency or hyperglycemia in vitro and in vivo.
Specific Aim 2 will determine if ECs contribute cells to calcific lesions using lineag tracing in two models of vascular calcification, the MGP-/- mouse and the diabetic Ins2Akita/+ mouse. For lineage tracing, the currently available Tie2-GFP or Tie2- Cre;R262R-eGFP transgenic mice will be used.
Specific Aim 3 will determine the relative contributions of EC- and SMC-specific loss of MGP in the development of vascular calcification using EC- and SMC-specific MGP knockout mice. If successful, the endothelium may emerge an important target to treat calcification in acquired vascular disease.

Public Health Relevance

Our studies are relevant to the treatment of disease of the heart and vessels, including hardening of the arteries and disease of vessels in diabetic patients. This study focuses on factors referred to as bone morphogenetic proteins, and how they can alter the vessel lining as to promote the hardening of the vessels. Understanding how these factors work may lead to new strategies for prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112839-02
Application #
8609059
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Reid, Diane M
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$346,500
Indirect Cost
$121,500
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Yao, Yucheng; Jumabay, Medet; Ly, Albert et al. (2013) A role for the endothelium in vascular calcification. Circ Res 113:495-504