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(American Journal of Pathology. 2004;165:1557-1570.)
© 2004 American Society for Investigative Pathology

Angiopoietin-1 Promotes Tumor Angiogenesis in a Rat Glioma Model

Marcia Regina Machein^*, Anette Knedla, Rolf Knoth, Shawn Wagner, Elvira Neuschl^* and Karl H. Plate

From the Department of Neurosurgery,^* University of Freiburg Medical School, Freiburg, Germany; the Institute of Neurology (Edinger Institute), University of Frankfurt Medical School, Frankfurt, Germany; the Department of Neuropathology, University of Freiburg Medical School, Freiburg, Germany; the Department of Experimental Cardiology, Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany

Angiopoietins have been implicated in playing an important role in blood vessel formation, remodeling, maturation, and maintenance. However, the role of angiopoietins in tumor angiogenesis remains uncertain. In this study, expression of human angiopoietin-1 (hAng-1) and angiopoietin (hAng-2) was amplified in the rat glioma cell line GS9L by stable transfection using an inducible tet-off system. Transfected cells were implanted intracerebrally into syngenic Fischer 344 rats. We demonstrated by means of magnetic resonance imaging that increased hAng-1 expression promoted a significant in vivo growth of intracerebral gliomas in rats. Overexpression of hAng-1 resulted in more numerous, more highly branched vessels, which were covered by pericytes. On the other hand, tumors derived from hAng-2-overexpressing cells were smaller than empty-plasmid control tumors. The tumor vasculature in these tumors was composed of aberrant small vascular cords, which were associated with few mural cells. Our results indicate that in the presence of hAng-1, tumors induce a more functional vascular network, which led to better tumor perfusion and growth. On the other hand, overexpression of hAng-2 led to less intact tumor vessels, inhibited capillary sprouting, and impaired tumor growth.

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