Pharmacologic and Genetic Manipulations of Angiotensin Signaling in Thoracic Aortic Disease Models

Thoracic aortic aneurysms and dissections (TAAD) are a major cause of morbidity and mortality in patients. Many different risk factors have been associated TAAD, but hypertension is the largest risk factor. Subsets of TAAD patients have identifiable syndromic genetic diseases, yet a number of genetic non-syndromic patients have been identified. Infusion of angiotensin II into mouse models causes aortic disease through inflammation and fibrosis. An angiotensin type I receptor (AT1R) blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor (ACEi) can reverse aortic pathology in some mouse models. I set out to better understand the relationship between angiotensin and TAAD in our mouse models, and hypothesized that angiotensin II signaling through the AT1R contributes to thoracic aortic aneurysm formation in multiple model systems of disease, and that blocking related receptors in addition to the AT1R, such as the AT2R and Mas receptor, may have negative consequences. Previously identified genetic variants in the gene encoding smooth muscle alpha-actin, ACTA2, were modeled with Acta2-/- mice. I found that the ascending aorta and aortic root in these mice become significantly dilated over time. Acta2-/- mice are hypotensive, and increasing the blood pressure with a pharmaceutical and diet based regimen significantly accelerated and worsened the aortic phenotype. Treatment with losartan, an ARB, attenuated the aortic dilation, but captopril, an ACEi, did not decrease aortic growth and worsened the disease. Transverse aortic constriction (TAC) was used to study the ascending aorta and aortic root in response to increased biomechanical forces. Losartan attenuated the histologic and inflammatory changes associated with TAC, but captopril was again unable to rescue the phenotype. To understand why, I investigated other receptors blocked by ACEis: the angiotensin II type 2 receptor (AT2R) and the Mas receptor, a receptor for the Ang1-7 peptide. I found that cotreatment with captopril and an agonist for the AT2R had similar physiologic effects as the AT1R blocker despite being unable to prevent the fibrotic and inflammatory remodeling. In contrast, cotreatment with captopril and an agonist for the Mas receptor blocked remodeling but did not rescue aneurysm formation. My results, coupled with clinical data, indicate that fibrosis may be beneficial in the aorta, and show we must expand our understanding of the angiotensin system in aortic disease