Artikel
Truncated PDGFalpha abolishes vasoconstriction in spontaneously hypertensive rats
Veränderungen des PDGFalpha Rezeptors verhindern die Vasokonstriktion bei spontanhypertensiven Ratten
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Autoren
Veröffentlicht: | 11. November 2004 |
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Gliederung
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Objective
Binding of platelet-derived growth factor (PDGF) to its receptors ( PDGFR-alpha/beta) initiates intracellular signaling pathways leading to proliferation of vascular smooth muscle cells (VSMC) or vasoconstriction.
Design and Methods
To determine whether mutations of truncated PDGFR-alpha functional domaine reduce the activation of the PDGFR¡Valpha in spontaneously hypertensive rats (SHR), we constructed truncated PDGFR-alpha by gene recombination (Ad5CMV-PDGFR-alpha). Immunoblotting was used to assess tyrosine phosphorylation of PDGFR-alpha immunoprecipitated from cultured rat aortic VSMC, which were transfected with either empty vector for control or transfected with PDGFR-alpha encoding adenoviruses. Incorporation of 3H-thymidine and 3H-Leucine was measured, and intracellular free calcium in VSMC was obtained using fura-2 spectrofluorometry. Vascular reactivity of aortic rings was studied using an isometric force transducer.
Results
Truncated PDGFR-ƒÑ (Ad5CMV-PDGFR-alpha) significantly reduced PDGF-mediated 3H-thymidine incorporation into VSMC compared to control values (160¡Ó7Bq/well vs 204¡Ó9 Bq/well, mean¡ÓSEM, each n=8, p<0.05). Truncated PDGFR-alpha significantly reduced PDGF-mediated 3H-Leucine incorporation into VSMC compared to control values (722¡Ó42Bq/well vs 1027¡Ó32 Bq/well, each n=8, p<0.05). The PDGF¡Vinduced increase of intracellular free calcium concentration was significantly lower in VSMC transfected with truncated PDGFR-alpha compared with controls (108¡Ó9 nmol/L vs 218¡Ó7 nmol/L, n=10, p<0.01). On the other hand, insulin-induced proliferation of VSMC was not significantly reduced in VSMC transfected with truncated PDGFR-alpha. Reactivity of aortic rings to angiotensin II stimulation was significantly reduced after incubation with truncated PDGFR-alpha receptor encoding adenoviruses for 4 hours (0.14¡Ó0.03g vs 0.17¡Ó0.03g, n=6, p<0.01).
Conclusion
Truncated PDGFR-alpha reduces vasconstriction and vascular growth in primary hypertension.