These studies demonstrate low expression of TSP in early wounds when max imal vascular proliferation is obser ved, and strong TSP expression in late wounds at the onset of and during vascular regression. In summar y, the experiments reported here establish TSP as a potent inhibitor of tumor grow th and angiogenesis in vivo.Prev iously, it was suggested that the antiangiogen ic ef fect of the related molecule TSP is partly mediated through interaction of the CSVTCG sequence, containedwithin the properdinlike type I repeats,with the CD receptor on endothelial cells. A lthough the importance of this interaction for the biological activ ity of TSP still has to be established, it is of interest that TSP also contains two CSVTCG domainswithin the type I repeats.In addition, analysis of proteoly tic fragments of the TSP molecule revealed antiangiogen ic activ ity of peptides derived from the procollagenlike domain, in particular the peptide NGVQYRN. This sequence is absent from the procollagenlike domain of TSP, which shows relatively low homologyw ith TSP, and we are currently investigating whether additional active sites residewithin this domain of the TSP molecule.This finding may ref lect dif ferences in the molecular stability or protease resistance of the two molecules in vivo, or it may be related to dif ferences in the responsiveness of endothelial cells of dif Betamethasone ferent organs.Indeed, the migration of microvascular endothelial cells derived from the human dermis was inhibited more potently by TSP CM than by TSP CM. Moreover, mice deficient for TSP demonstrate a more pronounced increase in the number of sk in blood vessels. Similar to the recently reported synergistic antitumoral ef fects of combined angiostatin and endostatin therapy, combined expression of TSP and TSP completely suppressed squamous cell carcinoma development, suggesting that a combination of angiogenesis inhibitors may prov ide better therapeutic ef ficiency than single agent therapy.However, further research is needed to evaluate the relative importance of distinct antiangiogen ic factors and to establish optimized combinations of dif ferent classes of angiogenesis inhibitors. uno. u Loss of Silver sulfadiazine endoglin caused poor vascular smooth muscle development and arrested endothelial remodeling.These results demonstrate that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT.HHT is an autosomal dominant vascular dysplasia characterized by recurrent epistaxis, telangiectasia, gastrointestinal hemorrhage, and pulmonary, cerebral, and hepatic arteriovenous malformations. The second stage of vascular development, angiogenesis, involves remodeling the primary endothelial network into a mature circulatory system. To understand the role of endoglin in vascular development, we used gene targeting to generate mice lacking endoglin.The targeting vector was designed to replace the first two exons with a gene that conferred neomycin resistance cell clones were identified and used to generate chimeric mice by morula aggregation.Southern blot analysis confirmed germ line transmission of the targeted allele. Cross sections of asmc actin immunostains identified vsmc between the endoderm and endothelium of the yolk sac.These data support our conclusion that endoglin is required for normal vsmc development.Angiogenesis involves the differential growth and sprouting of endothelial tubes and recruitment and differentiation of mesenchymal cells into vsmc and pericytes.

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