Abstract TAC299: A Novel Model of Sustained Hypertension Using an AngII Adeno-Associated Virus

Hypertension is a prevalent cardiovascular disease and a leading risk factor for vascular diseases such as aneurysm and stroke, with an estimated impact of 7.5 million deaths per year. Developing and improving models of hypertension is a critical step in the investigation of novel mechanisms driving cardiovascular disease. Our goal was to use an Adeno-Associated Virus (AAV)-based approach because of the long-term stability of AAV episomes in mice, as well as their ease of use in combination with other genetic or surgical models to mimic comorbid conditions such as obesity or hyperlipidemia. AAV approaches provide improved opportunities for the temporal control of blood pressure and ease of use versus the need for surgical implantation of angiotensinII (AngII) minipumps. Our approach was to use an AAV2/8 capsid that enables liver specific transduction and non-invasive measurements of blood pressure using radio telemetry. In initial experiments we constructed AAVs expressing renin and renin2 as well as modified renin isoforms, but these approaches did not robustly elevate blood pressure. Subsequently we made a liver specific AAV that enables the release of AngII directly from the liver into the circulation, activating the Angiotensin Type 1 receptor (AT1) to promote chronic vasoconstriction and elevated blood pressure. At a dose of 1e11 genome copies and IV administration, our AngII AAV resulted in a robust increase in systolic blood pressure that peaked ~200 mmHg. Blood pressure elevation was sustained at 8 weeks post-injection, and diurnal blood pressure patterns were preserved. The mechanism of AT1 activation was validated using Losartan, an AT1 receptor blocker, which reversed the elevated blood pressure. We next assessed changes in the mechanical properties of blood vessels from mice treated with the AngII AAV. We found increased pulse wave velocity and vessel area of the aorta, consistent with increased stiffness, hypertrophy, and remodeling, and greater expression of AT1. The heart and kidneys also underwent hypertrophy, with elevated markers of fibrosis in the kidneys of AngII AAV mice. The AngII AAV model is a versatile and practical tool to facilitate studies of hypertension and its related pathologies.