ANG II type 2 receptor regulates smooth muscle growth and force generation in late fetal mouse development.
Although evidence from culture studies implicates the angiotensin II (ANG II) type 2 receptor (AT(2)R) in the regulation of growth and differentiation of arterial smooth muscle (SM) cells (SMC), the lack of its expression in adult arteries has precluded direct investigation of its role in vivo. The goal of the present study was to determine the role of AT(2)R in the control of fetal SMC growth, contractility, and differentiation during vascular development. Determination of isometric tension in fetal aortas showed potentiated ANG II-induced contraction by treatment with the selective AT(2)R antagonist PD-123319, demonstrating the presence of functional AT(2)Rs that mediate reduced force development in vascular SMC. In direct contrast to numerous cell culture studies, proliferation indexes were decreased rather than increased in aortic SMC of fetal homozygous AT(2)R knockout compared with wild-type or heterozygous knockout mice. Experiments using SMC tissues from heterozygous female AT(2)R knockout mice, which are naturally occurring chimeras for AT(2)R expression, showed that AT(2)R mRNA expression was exactly 50% of that of wild type. This indicated that loss of AT(2)R expression did not confer a selective advantage or disadvantage for SMC lineage determination and expansion. Real time RT-PCR analyses showed no significant difference in expression of SM-alpha-actin, SM myosin heavy chain, and myocardin in various SM tissues from all three genotypes, suggesting that knockout of AT(2)R had no effect on subsequent SMC differentiation. Taken together, results indicate that functional AT(2)R are expressed in fetal aorta and mediate reduced force development but do not significantly contribute to regulation of SMC differentiation.
Perlegas
Demetra
D
Department of Molecular Physiology and Biological Physics, University of Virginia, PO Box 801394, Charlottesville, VA 22908-1394, USA.
Xie
Hui
H
Sinha
Sanjay
S
Somlyo
Avril V
AV
Owens
Gary K
GK
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000196:embryology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D005260:Female; D047109:Fetal Development; D005333:Fetus / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000196:embryology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000099251:Myocardin
D000199:Actins; D000804:Angiotensin II; D018995:Myosin Heavy Chains; D009687:Nuclear Proteins; D044139:Receptor, Angiotensin, Type 2; D015534:Trans-Activators; D014662:Vasoconstrictor Agents; D000099251:Myocardin