G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras.
The binding of vasoactive peptides to their respective G protein-coupled receptors has been implicated in the pathogenesis of vascular smooth muscle cell proliferation, leading to the development of hypertension, arteriosclerosis, and restenosis after vascular injury. We previously showed that the cytosolic tyrosine kinase pp60c-src is crucial for angiotensin II (ANG II)-induced activation of the protooncogene p21ras. Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors. ANG II, endothelin-1, or thrombin increased cell proliferation and DNA synthesis. Electroporation of anti-pp60c-src antibodies into cells abolished proliferation in response to these G protein-coupled receptor ligands but not in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, electroporation of anti-p21ras antibody completely blocked DNA synthesis and cell proliferation in response to ANG II, endothelin-1, thrombin, and PDGF-BB. Our data indicate that the pp60c-src tyrosine kinase is necessary and specific for vascular smooth muscle cell proliferation and DNA synthesis in response to G protein-coupled receptors but not classic growth factor receptors.
Schieffer
B
B
Division of Cardiology, Hannover Medical School, Germany.
Drexler
H
H
Ling
B N
BN
Marrero
M B
MB
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001011:Aorta; D000077214:Becaplermin; D001713:Biphenyl Compounds / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D018274:Electroporation; D019332:Endothelin-1 / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000502:physiology; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D000906:Antibodies; D001713:Biphenyl Compounds; D019332:Endothelin-1; D007093:Imidazoles; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D018179:Receptors, Thrombin; D013777:Tetrazoles; D000804:Angiotensin II; D000077214:Becaplermin; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; D016392:Proto-Oncogene Proteins pp60(c-src); D013917:Thrombin; D019204:GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D019808:Losartan