Therapeutic advances in cardiovascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) are emerging as essential regulators of the vasculature, important in disorders such as arteriovenous malformations (AVMs) and diabetic vasculopathy. Our data show that endothelial BMP4 activity causes a sequential induction of two BMP inhibitors, Matrix Gla Protein (MGP) and Crossveinless-2 (Cv2). MGP inhibits BMP4, and when deficient, allows the emergence of stem cell markers in the endothelium, vascular calcification, and AVMs. Deficiency of Cv2 leads to an abnormal and thickened endothelium, without the increase in stem cell markers. Our data suggest a 2-step model where MGP regulates proliferation and stem cell characteristics in vascular progenitor cells, and Cv2 regulates proliferation and maturation of committed ECs. In this 2-step model, we hypothesize that BMP4 and MGP regulate the size of the vascular progenitor pool, whereas BMP9 and Cv2 regulate the size of the committed EC pool. Thus, enhanced BMP4 activity or decreased MGP would allow for osteogenesis in the multipotent progenitor cells leading to vascular calcification. Both MGP and Cv2 may play important roles in the regulation of diabetic microvascular abnormalities and AVMs. We hypothesize that by manipulating MGP and Cv2, we will be able to inhibit the vascular abnormalities in which these inhibitors play a role.
Specific Aim 1 will test the validity of a 2-step model of EC lineage differentiation in vitro and in vivo. The model predicts that elevating the level of MGP will limit excessive endothelial growth resulting from Cv2 deficiency.
Specific Aim 2 will determine the contribution of MGP and Cv2 to the formation of AVMs in a mouse model of hereditary hemorrhagic telangiectasia (HHT). Our model predicts that increasing BMP inhibition through MGP or Cv2 will limit the signs of HHT.
Specific Aim 3 will determine the mechanism by which BMP inhibition could regulate diabetic vasculopathy. MGP and Cv2 are predicted to be stage-specific BMP inhibitors, and inadequate BMP inhibition would allow for vascular pathology in the aorta and the microvasculature as modeled by the diabetic Ins2Akita/+ mouse. If successful, the obtained information may translate into strategies for using BMP inhibitors in treating vascular disease.

Public Health Relevance

Our studies are relevant to the treatment of disease of the heart and vessels such as hardening of the arteries, which is common in patients with diabetes, and hereditary hemorrhagic telangiectasia, a hereditary disease. Our studies focus on factors called bone morphogenetic proteins and their inhibitors, which are important in regulating the heart and 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 #
2R01HL081397-06A1
Application #
8292985
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
2005-07-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$135,000
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
Yao, Jiayi; Guihard, Pierre J; Blazquez-Medela, Ana M et al. (2016) Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells. Angiogenesis 19:1-7
Boström, Kristina I; Yao, Jiayi; Guihard, Pierre J et al. (2016) Endothelial-mesenchymal transition in atherosclerotic lesion calcification. Atherosclerosis 253:124-127
Boström, Kristina I (2016) Where do we stand on vascular calcification? Vascul Pharmacol 84:8-14
Blazquez-Medela, Ana M; Guihard, Pierre J; Yao, Jiayi et al. (2015) ABCC6 deficiency is associated with activation of BMP signaling in liver and kidney. FEBS Open Bio 5:257-63
Yao, Jiayi; Guihard, Pierre J; Blazquez-Medela, Ana M et al. (2015) Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification. Circ Res 117:758-69
Jumabay, Medet; Moon, Jeremiah H; Yeerna, Huwate et al. (2015) Effect of Diabetes Mellitus on Adipocyte-Derived Stem Cells in Rat. J Cell Physiol 230:2821-8
Demer, Linda L; Boström, Kristina I (2015) Conflicting forces of warfarin and matrix gla protein in the artery wall. Arterioscler Thromb Vasc Biol 35:9-10
Boström, Kristina I; Guihard, Pierre; Blazquez Medela, Ana M et al. (2015) Matrix Gla protein limits pulmonary arteriovenous malformations in ALK1 deficiency. Eur Respir J 45:849-52
Jumabay, Medet; Boström, Kristina I (2015) Dedifferentiated fat cells: A cell source for regenerative medicine. World J Stem Cells 7:1202-14
Jumabay, Medet; Abdmaulen, Raushan; Ly, Albert et al. (2014) Pluripotent stem cells derived from mouse and human white mature adipocytes. Stem Cells Transl Med 3:161-71

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