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(Circulation Research. 2006;99:257.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Identification of Sokotrasterol Sulfate As a Novel Proangiogenic Steroid

Siun Murphy^*, Bruno Larrivée^*, Ingrid Pollet, Kyle S. Craig, David E. Williams, Xin-Hui Huang, Megan Abbott, Fred Wong, Cameron Curtis, Thomas P. Conrads, Timothy Veenstra, Mira Puri, York Hsiang, Michel Roberge, Raymond J. Andersen, Aly Karsan

From the Departments of Medical Biophysics (S.M., B.L., I.P., M.A., F.W., C.C., A.K.) and Pathology & Laboratory Medicine (A.K.), British Columbia Cancer Agency, Vancouver, Canada; Departments of Chemistry (K.S.C., D.E.W., X.-H.H., R.J.A.), Surgery (Y.H.), Biochemistry and Molecular Biology (M.R.), and Pathology & Laboratory Medicine (A.K.), University of British Columbia, Vancouver, Canada; Laboratory of Proteomics and Analytical Technologies (T.P.C., T.V.), SAIC-Frederick Inc, National Cancer Institute at Frederick, Md; and Department of Medical Biophysics (M.P.), Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada.

Correspondence to Aly Karsan, Department of Medical Biophysics, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3, Canada. E-mail akarsan{at}bccrc.ca

The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2ß,3,6-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of _vß₃ integrin was also necessary for function, as neutralization of _vß₃ integrin, but not ß₁ integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.

Key Words: angiogenesis • ischemia • endothelium

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