Angiogenesis pp 285-296 | Cite as

Endogenous Regulation of Angiogenesis in Vitro

  • Roberto F. Nicosia
Part of the NATO ASI Series book series (NSSA, volume 298)


Rings of rat aorta embedded in collagen gel and cultured under serum-free conditions produce a self-limited angiogenic response in the absence of exogenous growth factors. Aortic rings respond to the injury of the dissection procedure by generating outgrowths of branching microvessels and fibroblasts. The microvessels originate primarily from the aortic intima whereas fibroblasts arise from the adventitia. The endothelium of the rat aorta switches to a microvascular phenotype and recruits pericytes from a subpopulation of smooth muscle cells located in the intimal/subintimal layers. Formation of microvessels is due to the combined effect of injury, exposure of the apical surface of the endothelium to a hydrated collagen matrix, and paracrine interactions between endothelial and nonendothelial cells. Endogenous growth factors involved in the regulation o angiogenesis include basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF). and platelet-derived growth factor (PDGF). bFGF and VEGF stimulate angiogenesis directly. PDGF stimulates fibroblasts and pericytes, which in turn modulate the growth, differentiation and survival of microvessels. Fibroblasts, which are the first cells to migrate out of the expiants, promote angiogenesis by secreting growth factors and by stabilizing the newly formed microvessels. Pericytes, which increase in number during the maturation of the microvessels, contribute to the differentiation and remodeling of the neovasculature. These results indicate that the rat aorta model can be used to study the cellular and molecular mechanisms by which the vessel wall regulates microvessel formation at different stages of the angiogenic process.


Vascular Endothelial Growth Factor Aortic Ring Angiogenic Response Exogenous Growth Factor Endogenous Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Brogi, E., Wu, T., Namiki, A., and Isner J.M., 1994, Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation, 90:649–652PubMedCrossRefGoogle Scholar
  2. Brown, J., Maynes, S.F., Bezos, A., Maguire, DJ., Ford, M.D., and Parish, R., 1996, A novel in vitro assay of human angiogenesis, Lab. Invest.75:539–555.PubMedGoogle Scholar
  3. Clark, E.R., and Clark, E.L., 1925, The development of adventitial (Rouget) cells on the blood capillaries of amphibian larvae, Am J. Anat.35:239–264.CrossRefGoogle Scholar
  4. Ferrara, N., Houck, K., Jakeman, L., and Leung D., 1992, Molecular and biological properties of the vascular endothelial growth factor. Endocr Rev, 13:18–32.PubMedGoogle Scholar
  5. Folkman, J., Shing, Y., 1992, Angiogenesis, J. Biol. Chem.267:10931–10934.PubMedGoogle Scholar
  6. Fox, P.L. and Di Corleto, P.E., 1991, Endothelial cell production of platelet derived growth factor, Seminars in Perinatol.15:34–39.Google Scholar
  7. Gabbiani, G., Ryan, G.B. and Majno, G, 1971, Presence of modified fibroblasts in granulation tissue and their role in wound contraction, Experientia, 27:549–550.PubMedCrossRefGoogle Scholar
  8. Kawasaki, S., Mori M., Awai M., 1989, Capillary growth of rat aortic segments cultured in collagen without serum. Acta Pathol Japonica 39:712–718.Google Scholar
  9. Lindner, V. and Reidy, M.A., 1995, Platelet-derived growth factor ligand and receptor expression by large vessel endothelium in vivo, Am. J. Pathol.146:1488–1497.PubMedGoogle Scholar
  10. Majesky, M.W., Reidy, M.A., Bowen-Pope, D.F., Hart, C. E., Wilcox, J. N., Schwartz, S.M., 1990, PDGF ligand and receptor gene expression during repair of arterial injury, J. Cell Biol, 111:2149–2158.PubMedCrossRefGoogle Scholar
  11. Merwin, J.R., Anderson, J.M., Kocher, O., Van Itallie, C.M., and Madri, J.A., 1990, Transforming growth factor beta-1 modulates extracellular matrix organization and cell-cell junctional complex formation during in vitro angiogenesis, J Cell Physiol, 142:117–128.PubMedCrossRefGoogle Scholar
  12. Nicosia, R.F., 1997, The rat aorta model of angiogenesis and its applications, in Vascular Morphogenesis in Vivo, in Vitro and in Sapio, (Little, H. Sage and V. Mironov eds), Birkhauser, Cambrige, MA (in press)Google Scholar
  13. Nicosia, R.F., Lin Y.J., Hazelton D., Quian, X., 1996, Role of vascular endothelial growth factor in the rat aorta model of angiogenesis, J. Vase. Res.33 (SI): 73Google Scholar
  14. Nicosia, R. F., Nicosia S. V. and Smith, M, 1994a, Vascular endothelial growth factor, platelet derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro, Am. J. Pathol.145:1023–1029PubMedGoogle Scholar
  15. Nicosia, R. F., Ottinetti A., 1990, Growth of microvessels in serum-free matrix culture of rat aorta: a quantitative assay of angiogenesis in vitro. Lab. Invest.63:115–122.PubMedGoogle Scholar
  16. Nicosia, R.F., Villaschi, S., 1995, Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro, Lab. Invest.73:658–666PubMedGoogle Scholar
  17. Nicosia, R.F., Bonanno, E., Villaschi, S., 1992, Large-vessel endothelium switches to a microvascular phenotype during angiogenesis in collagen gel culture of rat aorta. Atherosclerosis, 95:191–199.PubMedCrossRefGoogle Scholar
  18. Nicosia, R. F., Villaschi, S., Smith, M. 1994b, Isolation and characterization of vasoformative endothelial cells from the rat aorta, In Vitro Cell. Dev. Biol.30A:394–399CrossRefGoogle Scholar
  19. Orlidge, A. and D’Amore, P., 1987, Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells, J Cell Biol, 105:1455–62PubMedCrossRefGoogle Scholar
  20. Rhodin, J.A.G. and Fujita, H., 1989, Capillary growth in the mesentery of normal young rats. Intravital vdeo and electron microscope analysis, J. Submicroscop. Cytol Pathol.21:1–34.Google Scholar
  21. Sato, N., Beitz, J.G., Kato, J., Yamamoto, M., Clark, J.W., Calabresi, P., and Frackelton, R. Jr., 1993, Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am. J.Pathol. 4:1119–1130.Google Scholar
  22. Sato, Y., Rifkin, D.B., 1989, Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of latent transforming growth factor beta-1-like molecule by plasmin during co-culture. J Cell Biol, 109:309–15.PubMedCrossRefGoogle Scholar
  23. Schiffers, P. M. H., Fazzi, G. E., van Ingen Schenau, D. and De Mey, J. G R., 1994, Effects of candidate autocrine and paracrine mediators of growth responses in isolated rat arteries, Arterioscler. Thromb.14:420–426.PubMedCrossRefGoogle Scholar
  24. Villaschi S. and Nicosia R.F., 1993, Angiogenic role of basic fibroblast growth factor released by rat aorta after injury, Am. J. Pathol.143:182–190.Google Scholar
  25. Villaschi, S., Nicosia, R.F., 1994, Paracrine interactions between fibroblasts and endothelial cells in a serum-free co-culture model: modulation of angiogenesis and collagen gel contraction. Lab. Invest.71:291–299.PubMedGoogle Scholar
  26. Villaschi, S., Nicosia, R.F., Smith, M., 1994, Isolation of a morphologically and functionally distinct muscle cell type from the intimai aspect of the normal rat aorta. Evidence for smooth muscle cell heterogeneity, In Vitro Cell. Dev. Biol.30A: 589–595CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Roberto F. Nicosia
    • 1
  1. 1.Department of PathologyAllegheny University of the Health SciencesPhiladelphiaUSA

Personalised recommendations