Angiogenesis, i.e. the formation of blood vessels by endothelial cells, plays an important role in the pathogenesis of several vascular diseases and of tumor growth. The goal of this study is to elucidate the role of the extracellular matrix (ECM) in the regulation of angiogenesis. Studies from our laboratory and from others have shown that fibronectin, laminin and type IV collagen, which are major components of the microvascular ECM, accumulate around developing microvessels in different amounts at different, i stages of angiogenesis. These molecules have distinct effects on the attachment, spreading, migration and proliferation of endothelial cells on two-dimensional plastic surfaces but their function during angiogenesis in three-dimensional gels of fibrin or type I collagen, i.e. in a setting that simulates the in vivo environment is poorly understood. Our hypothesis is that the growth and morphogenesis of microvessels is modulated by changes in the composition of the microvascular ECM during angiogenesis. To investigate this hypothesis we will use the rat aortic ring model of angiogenesis in vitro, which was first developed in our laboratory. Rings of rat aorta or isolated endothelial cells will be cultured in chemically defined gels of fibrin or type I collagen containing known amounts of fibronectin, laminin and/or type IV collagen. Angiogenesis will be evaluated using image analysis, autoradiographic and immunohistochemical techniques. The reconstituted matrices will be characterized with electro- phoretic,Western blotting and immunohistochemical techniques.
Specific aims : 1. To determine the concentrations of fibronectin, laminin or type IV collagen that have a maximum stimulatory or inhibitory effect on the sprouting, canalization and maturation of microvessels and to investigate if these molecules have additive, synergistic or antagonistic effects on angiogenesis. 2. To investigate the hypothesis that fibronectin, laminin and/or type IV collagen regulate angiogenesis by influencing the direction of endothelial sprouting. 3. To evaluate the effect of fibronectin, laminin and/or type IV collagen on the attachment, spreading and proliferation of isolated endothelial cells in gels of fibrin or type I collagen.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL043392-02
Application #
3472828
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-08-01
Project End
1994-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Pierro, E; Nicosia, S V; Saunders, B et al. (1996) Influence of growth factors on proliferation and morphogenesis of rabbit ovarian mesothelial cells in vitro. Biol Reprod 54:660-9
Nicosia, S V; Diaz, J; Nicosia, R F et al. (1995) Cell proliferation and apoptosis during development and aging of the rabbit corpus luteum. Ann Clin Lab Sci 25:143-57
Villaschi, S; Nicosia, R F; Smith, M R (1994) Isolation of a morphologically and functionally distinct smooth muscle cell type from the intimal aspect of the normal rat aorta. Evidence for smooth muscle cell heterogeneity. In Vitro Cell Dev Biol Anim 30A:589-95
Nicosia, R F; Nicosia, S V; Smith, M (1994) Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol 145:1023-9
Nicosia, R F; Bonanno, E; Smith, M et al. (1994) Modulation of angiogenesis in vitro by laminin-entactin complex. Dev Biol 164:197-206
Villaschi, S; Nicosia, R F (1994) Paracrine interactions between fibroblasts and endothelial cells in a serum-free coculture model. Modulation of angiogenesis and collagen gel contraction. Lab Invest 71:291-9
Nicosia, R F; Villaschi, S; Smith, M (1994) Isolation and characterization of vasoformative endothelial cells from the rat aorta. In Vitro Cell Dev Biol Anim 30A:394-9
Nicosia, R F; Tuszynski, G P (1994) Matrix-bound thrombospondin promotes angiogenesis in vitro. J Cell Biol 124:183-93
Tuszynski, G P; Nicosia, R F (1994) Localization of thrombospondin and its cysteine-serine-valine-threonine-cysteine-glycine-specific receptor in human breast carcinoma. Lab Invest 70:228-33
Villaschi, S; Nicosia, R F (1993) Angiogenic role of endogenous basic fibroblast growth factor released by rat aorta after injury. Am J Pathol 143:181-90

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