Hypertension-induced cardiovascular diseases remain the major cause of death worldwide. While endothelial dysfunction is an important mediator of hypertension-induced vascular remodeling, mechanisms by which it contributes to the remodeling are not fully understood.

We studied the pathophysiological role of endothelial angiotensin receptor type 1 (AT1R) / Akt1 signaling in the development of vascular remodeling during hypertension.

We employed two mice models, one lacking both isoforms of AT1 receptors on endothelial cells (AT1aR^EC-/-xAT1bR^-/-) and a second model lacking endothelial Akt1 (Akt1^Tie2-/-). To induce hypertension, mice were infused with 1.5 mg/kg/day ANGII using osmotic minipumps for 4-weeks. Systolic blood pressure (SBP) was measured using the tail-cuff method. After 4 weeks, vascular remodeling was assessed using histology and endothelial function was measured using Mulvany myography. Matrix metalloproteinase 2 (MMP2) activity was determined with gelatin zymography and inflammatory cell count in vascular tissue by flow cytometry.

ANGII-infused AT1aR^EC-/-xAT1bR^-/- mice had ~12 mmHg lower SBP compared to WT mice. The mice were protected from vascular remodeling and showed less aortic hypertrophy (P<0.01) and fibrosis (P<0.01). AT1aR^EC-/-xAT1bR^-/- mice had more elastin (P<0.05) content and less MMP2 activity (P<0.01) in aorta. Endothelium-dependent relaxation was ~35 % greater in AT1aR^EC-/-xAT1bR^-/- compared to WTs. Inflammatory cell count (CD45+, TCR-β+, CD4+ and CD8+ cells) was lower in aorta of AT1aR^EC-/-xAT1bR^-/- mice (P<0.01) compared to WT mice. Mice lacking only one isoform of AT1R - AT1aR^wt/wtxAT1bR^-/- or AT1aR^EC-/-xAT1bR^wt/wt mice were not protected and did not differ from WT mice. Akt1^EC-/- mice showed a similar protective vascular phenotype as AT1aR^EC-/-xAT1bR^-/- mice. Experiments with human aortic cells confirmed the importance of the AT1R/Akt1 axis in vascular remodeling. MMP2 activity was significantly (P<0.01) lower in ANGII-stimulated human aortic smooth muscle cells co-cultured with endothelial cells where Akt1 was silenced compared to control. Supplementation of endothelin-1 (ET1) reversed this effect and led to activation of MMP2. Inhibition of ETa, but not ETb receptor, on smooth muscle cells blocked the activation of MMP2 in these cells. Experiments on isolated human aorta showed that ANGII-stimulated aortas without endothelium had less (P<0.01) MMP2 activity compared to aortas with endothelium. Addition of ET1 reversed this effect, whereas inhibition of ETa, but not ETb, receptor blocked the activation of MMP2.

We demonstrate that the endothelial AT1R/Akt1 axis mediates ANGII-induced endothelial dysfunction, which causes ET1/ETa receptor dependent activation of MMP2. This axis appears to be the mechanistic link for enhanced vascular inflammation and consequent remodeling. Our findings advance the understanding of ANGII-induced endothelial dysfunction and its contribution to vascular remodeling.