Attenuated Angiotensin Ii-Response in Transgenic Mice Expressing the At1 Receptor in the Vascular Endothelial Cells.
The angiotensin II AT1 receptor mediated vasoconstriction is believed to be due to direct stimulation of vascular smooth muscle cells by the hormone angiotensin II (AngII). Recent evidence suggests that AT1 receptors, also expressed on endothelial cells (EC), on stimulation couple to activation of Ca+2 calmodulin-dependent nitric oxide synthase and NO release in vitro. These AT1 receptors may mediate a vasodilatory function in the endothelium in vivo, contributing to regulatory mechanisms in blood pressure control. To investigate the physiological role of AT1 receptors on ECs, we generated transgenic mice expressing a constitutively active AT1[N111G] receptor specifically in vascular ECs using the mouse tie gene promoter. Of the three tie-AT1 founder lines with varying copies of transgene, two (TG23 and TG26) showed EC-specific transgene RNA transcript, and receptor protein expression when stained with an epitope-specific antibody. Increased mortality complemented with lack of homozygosity was observed in heterozygous TG23 mice. Tail-cuff systolic blood pressures measured were significantly reduced in TG23 tie-AT1 mice (116±2 TG versus 142±2 control) suggesting a vasodilatory effect mediated by the transgenic receptor. Change in arterial pressure to infused AngII (1 μg/kg body wt.) measured was depressed by approx. 40 % in TG23 tie-AT1 mice compared to controls, and a lower dose (0.2 μg/kg body wt.) evoked no response. These results suggest that the AngII-mediated response in vivo seems to depend on the cell types of the vascular beds and their downstream signaling events which may have important regulatory functional consequences.