Integrin alpha1 null mice as genetic model to study skin disease

Vanderbilt University, Nashville TN

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Abstract

Angiogenesis, the process of new blood vessel formation, is required for both physiological and pathological events including wound healing and tumor growth. Angiogenesis is proposed by various effectors including growth factors. In physiological situations, when sufficient neovascularization has occurred and angiogenesis needs to stop, angiogenic factors are down-regulated or the concentration of natural inhibitors increases. Endothelial cell proliferation can be inhibited by a number of factors, the most potent and best known of which is angiostatin, a cleavage product of plasminogen. Angiostatin is generated by various enzymes including members of the matrix metalloproteinase (MMPs) family. Angiostatin have been successfully used in vivo to prevent primary tumor growth. In this context, we showed that in integrin alpha1-null mice tumor angiogenesis is reduced compared to that of wild type animals. This reduction is due to over-expression of MMPs in the alpha1-null and consequent generation of angiostatin from circulating plasminogen. Our findings., in contrast to the accepted role of MMPs being pro-tumorigenic, suggest that excess synthesis of MMPs may play opposite effects on tumor growth. On one hand, increased MMPs may promote cell migration and invasion facilitating matrix degradation. On the other hand, increased MMPs may prevent primary tumor growth promoting angiostatin synthesis. While the effects of angiostatin on the control of tumor vascularization are well documented, there are no data suggesting that MMP-generated angiostatin also influences endothelial cell growth during physiological events including wound healing. Thus we propose the following two aims in order to investigate the role of MMP/angiostatin axis in the control of neovascularization during physiological as well as pathological processes. We will: I) Determine in vivo i) the role of the MMP/angiostatin axis in the control of primary vs. metastatic human tumors, ii) whether MMP inhibitors can be successfully used in the prophylaxis of primary vs. metastatic cancers. II) Develop wound healing models, using the in vivo cutaneous window chamber assay, to determine whether the effects of angiostatin are limited to tumor angiogenesis, or they are also involved in the regulation of granulation tissue repair. These studies will enable us to determine how stimulation of the MMP/angiostatin axis can be used in vivo as a valid tool to regulate increased and uncontrolled neovascularization.