While fundamental to recovery from vascular occlusive events such as myocardial infarction, stroke, and peripheral vascular insufficiency, neovascular development also underlies the growth and progression of both benign and malignant tumors. In this proposal, we postulate that that the fibrinolytic receptor complex, known as the annexin 2/p11 system, promotes neoangiogenesis by supporting the development of key protease activities at the surface of vascular cells and their precursors. Specifically, we plan to focus on the role of annexin 2 (A2) in the recruitment and differentiation of vascular mural cells for stabilization of the developing neovessel. A2 belongs to a 60-member family of calcium-regulated, phospholipid-binding proteins expressed throughout the phylogenetic tree. We and others have identified A2 as the major endothelial cell fibrinolytic receptor that binds tissue plasminogen activator and its physiologic substrate, plasminogen. This assembly greatly accelerates plasmin generation, and promotes the dissolution of fibrin. Recently, we demonstrated that mice completely deficient in A2 have markedly impaired neoangiogenesis. New preliminary data substantiate and extend these findings by demonstrating a failure of tumor allograft growth in A2-null mice due to impaired tumor angiogenesis. We note specifically a paucity of neovessels, neovascular dilatation, and a deficiency of mural cells. Tumor-bearing A2-null mice display reduced circulating bone marrow derived VEGFR1+/CD11+ hematopoietic precursors, and tumor growth can be restored upon transplantation of A2-/- mice with A2+/+ marrow. We, therefore, hypothesize that expression of A2 on the surface of vascular cells and vascular precursor cells is essential for effective neoangiogenesis.
Our aims are to [1] determine whether A2 supports stabilization of new blood vessels by promoting recruitment of mural cells (pericytes and smooth muscle cells) to sites of angiogenesis in tumor-bearing mice and in humans with cancer, [2] determine whether PDGF-BB recruits mural cells to developing neovessels by stimulating translocation of the A2/p11 complex to the surface of mural cell precursors, [3] determine whether A2-supported angiogenesis also requires participation of its cofactor, p11, and [4] determine whether hyperhomocysteinemia impairs the angiogenic response by derivatizing A2 and blocking its protease-inducing activity. It is anticipated that new insights derived from these studies may lead to novel modalities in the diagnosis and treatment of neovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090895-04
Application #
8098802
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Gao, Yunling
Project Start
2008-08-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$422,500
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Chapin, John C; Hajjar, Katherine A (2015) Fibrinolysis and the control of blood coagulation. Blood Rev 29:17-24
Hajjar, Katherine A (2015) The Biology of Annexin A2: From Vascular Fibrinolysis to Innate Immunity. Trans Am Clin Climatol Assoc 126:144-55
Dassah, Maryann; Almeida, Dena; Hahn, Rebecca et al. (2014) Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells. J Cell Sci 127:828-44
Dai, Haibin; Yu, Zhanyang; Fan, Xiang et al. (2013) Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity. Thromb Haemost 109:1070-8
Ghajar, Cyrus M; Peinado, H├ęctor; Mori, Hidetoshi et al. (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15:807-17
Luo, Min; Hajjar, Katherine A (2013) Annexin A2 system in human biology: cell surface and beyond. Semin Thromb Hemost 39:338-46
Scharf, Brian; Clement, Cristina C; Wu, Xiao-Xuan et al. (2012) Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris. Nat Commun 3:755
Zhai, Haiyan; Acharya, Suchitra; Gravanis, Iordanis et al. (2011) Annexin A2 promotes glioma cell invasion and tumor progression. J Neurosci 31:14346-60
He, Kai-Li; Sui, Guangzhi; Xiong, Huabao et al. (2011) Feedback regulation of endothelial cell surface plasmin generation by PKC-dependent phosphorylation of annexin A2. J Biol Chem 286:15428-39
Upmacis, Rita K; Shen, Hao; Benguigui, Lea Esther S et al. (2011) Inducible nitric oxide synthase provides protection against injury-induced thrombosis in female mice. Am J Physiol Heart Circ Physiol 301:H617-24

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