The vascular system consists of elaborate networks that develop in combination with close regulation of endothelial cells (ECs). An understanding of such regulation is essential for the development of new treatment strategies aimed at vascular malformations, such as arteriovenous malformations (AVMs) and hereditary hemorrhagic telangiectasia (HHT), caused by mutations in activin receptor-like kinase 1 (ALK1). We previously showed that gene deletion in mice of matrix Gla protein (MGP), an inhibitor of bone morphogenetic proteins (BMPs), causes AVMs in multiple organs similar to HHT. We showed that BMP9/ALK1 signaling induces MGP expression in ECs, where MGP plays an important role in differentiation. BMP9/ALK1 signaling also induces Crossveinless-2 (CV2) with a different induction delay, thereby creating two negative feedback loops. Together, MGP and CV2 regulate BMP9 signaling by a previously unknown mechanism. In cultured ECs, we found oscillations of MGP and CV2 expression that temporally coordinated transition to EC stalk cell phenotype in ECs. This also caused markers of stalk cells to oscillate, whereas tip cell markers were suppressed. Deletion of Mgp abolished the oscillatory behavior. In vivo, MGP and CV2 were seen as ?shaping waves? or stripes in the growing retina, and lack of MGP perturbed the vascular networks. Our hypothesis is that MGP and CV2 are regulators of BMP9 signaling and vascular morphogenesis through generation of oscillations or waves of expression.
In Aim 1, we will characterize how MGP and CV2 orchestrate EC differentiation in response to BMP9 using oscillations of gene expression. We will relate BMP9-induced stalk cell phenotype to the oscillations, and explore expression profiles of ECs capable of this behavior. We will disrupt the system by deleting the Mgp gene in vitro using established techniques of shRNA, and determine the effect on the waves of inhibitors and stalk cell markers. We will also investigate whether waves of MGP and CV2 can be detected in normal vasculature, with focus on the retina.
In Aim 2, we will obtain key information about the role of MGP in retinal vascular networks and AVMs by deleting Mgp, impairing MGP protein function, and modulating the cellular origin. We will modulate potential targets for AVM treatments using the Mgp-/- mice as an AVM model. We will start with modulation of CV2 and use approaches that include crossbreeding with genetically altered mice and transmammary immunoblocking, and subsequently screen other factors in the BMP9 response. Our studies will help identify targets in the BMP9 response system that might be used in designing treatments for AVMs.

Public Health Relevance

Our studies are relevant to disease of the heart and vessels, including vessel malformations found in for example hereditary hemorrhagic telangiectasia. The goal is to understand a new type of regulation performed by inhibitors of the so-called bone morphogenetic proteins (BMPs), which are linked to normal as well as abnormal vessel formation. Such an understanding may be used to develop new strategies to treat disease in the heart and vessels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081397-13
Application #
9915958
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Jaquish, Cashell E
Project Start
2006-04-24
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
13
Fiscal Year
2020
Total Cost
Indirect Cost
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
Jumabay, Medet; Zhumabai, Jiayinaguli; Mansurov, Nurlan et al. (2018) Combined effects of bone morphogenetic protein 10 and crossveinless-2 on cardiomyocyte differentiation in mouse adipocyte-derived stem cells. J Cell Physiol 233:1812-1822
Boström, Kristina I; Yao, Jiayi; Wu, Xiuju et al. (2018) Endothelial Cells May Have Tissue-Specific Origins. J Cell Biol Histol 1:
Yao, Jiayi; Guihard, Pierre J; Wu, Xiuju et al. (2017) Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. J Cell Biol 216:3369-3385
Guihard, Pierre J; Yao, Jiayi; Blazquez-Medela, Ana M et al. (2016) Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice. PLoS One 11:e0167936
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
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; 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
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

Showing the most recent 10 out of 33 publications