Angiotensin AT1 receptor upregulates expression of basic fibroblast growth factor, basic fibroblast growth factor receptor and coreceptor in human coronary smooth muscle cells.
Autocrine stimulation and paracrine interaction between coronary smooth muscle cells (cSMC) and endothelial cells (EC) act as regulators of the vascular angiogenesis. Basic fibroblast growth factor (bFGF), its receptor FGF-R1, and coreceptor heparansulfate proteoglycan (HSPG) are important components involved in this angiogenic process. We investigated the influence of angiotensin (Ang) II on this trimolecular bFGF complex, the underlying signaling and the proliferative process in human cSMC. Ang II induces an AT1 receptor-dependent expression of bFGF and also upregulates the FGF-R1 and HSPG expression which is suppressed by losartan, the AT1 receptor blocker. AT1 receptor signaling which is characterized by phosphorylation of p42-mitogen-activated protein kinase (MAPK) is involved in Ang II-induced bFGF, FGF-R1 and HSPG upregulation and DNA synthesis in human cSMC. In contrast, inhibition of the AT2 receptor by PD123,319 has no influence on these Ang II-stimulated and via the MAPK cascade-mediated proangiogenic effects. Finally, our data show that the Ang II-induced DNA synthesis in cSMC is mediated via the bFGF expression. In conclusion, our results suggest that the Ang II-induced angiogenic effects in the vessel wall are supported by the AT1 receptor-stimulated and MAPK pathway-mediated upregulation of the autocrine/paracrine trimolecular bFGF complex in cSMC.
Skaletz-Rorowski
Adriane
A
Institute for Arteriosclerosis Research and Department of Cardiology and Angiology, Domagkstr. 3, 48149 Münster, Germany. skaletz@uni-muenster.de
Pinkernell
Kai
K
Sindermann
Jürgen R
JR
Schriever
Christoph
C
Müller
Joachim G
JG
Eschert
Heike
H
Breithardt
Günter
G
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D019898:Autocrine Communication; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019899:Paracrine Communication; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015854:Up-Regulation
D043925:Angiogenesis Inducing Agents; D019812:Heparan Sulfate Proteoglycans; D044140:Receptor, Angiotensin, Type 1; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020929:Mitogen-Activated Protein Kinase Kinases