(Hypertension. 2001;38:136.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Rescue of Impaired Angiogenesis in Spontaneously Hypertensive Rats by Intramuscular Human Tissue Kallikrein Gene Transfer
From the Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., T.S., L.G., P.M.), Osilo, Italy; Institutes of Internal Medicine (P.M.) and Epidemiology (A.P.), Medical University of Sassari, Sassari, Italy; and Department of Biochemistry and Molecular Biology, Medical University of South Carolina (J.C., L.C.), Charleston.
Correspondence to Costanza Emanueli, PhD, Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems (INBB), viale Sant’Antonio, 07033 Osilo (Sassari), Italy. E-mail emanueli{at}yahoo.com
Abstract—— Angiogenesis represents a compensatory response targeted to preserve the integrity of tissues subjected to ischemia. The aim of the present study was to examine whether reparative angiogenesis is impaired in spontaneously hypertensive rats (SHR), as a function of progression of hypertension. In addition, the potential of gene therapy with human tissue kallikrein (HK) in revascularization was challenged in SHR and normotensive Wistar-Kyoto rats (WKY) that underwent excision of the left femoral artery. Expression of vascular endothelial growth factor and HK was upregulated in ischemic hindlimb of WKY but not of SHR. Capillary density was increased in ischemic adductor muscle of WKY (from 266±20 to 633±73 capillaries/mm2 at 28 days, P<0.001), whereas it remained unchanged in SHR (from 276±20 to 354±48 capillaries/mm2, P=NS), thus compromising perfusion recovery as indicated by reduced plantar blood flow ratio (0.61±0.08 versus 0.92±0.07 in WKY at 28 days, P<0.05). In separate experiments, saline or 5x109 pfu adenovirus containing the HK gene (Ad.CMV-cHK) or the ß-galactosidase gene (Ad.CMV-LacZ) was injected intramuscularly at 7 days after the induction of ischemia. Ad.CMV-cHK augmented capillary density and accelerated hemodynamic recovery in both strains, but these effects were more pronounced in SHR (P<0.01). Our results indicate that native angiogenic response to ischemia is impaired in SHR, possibly as a result of defective modulation of endothelial cell mitogens. Supplementation with kallikrein, one of the growth factors found to be deficient in SHR, restores physiological angiogenic response utilitarian for tissue healing. Our discoveries may have important implications in vascular medicine for therapeutic benefit.
Key Words: angiogenesis • ischemia • genes • muscles • kallikrein
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