246 words Manuscript: 4100 words Number of Figures: 5 Supplemental Figures: 8 TOC category Basic TOC subcategory: Vascular Biology Highlights • Profound sexual dimorphism of aortic disease occurs in Fbn1 C1041G/+ mice, with female mice being more resistant and male mice being more susceptible. • Inhibition of the AngII-AT1aR axis attenuates aortic pathology in male Fbn1 C1041G/+ mice. • Antisense oligonucleotides targeting angiotensinogen deplete plasma angiotensinogen and attenuate thoracic aortic aneurysms.
Graphic Abstract
Abstract
Objective:A cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of ligand-dependent stimulation of angiotensin II receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1 C1041G/+ ).
Approach and Results:TAA in Fbn1 C1041G/+ mice were determined in both sexes and found to be strikingly sexual dimorphic. Males displayed progressive dilation over 12 months while ascending aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or -/-for AT1aR were generated. AT1aR deletion reduced progressive expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen (AGT-ASO) was administered to male Fbn1 C1041G/+ mice to determine the effects of angiotensin II depletion. AGT-ASO administration, at doses that markedly reduced plasma AGT concentrations, attenuated progressive dilation of the ascending aorta and aortic root. AGT-ASO also reduced medial thickening and elastin fragmentation.
Conclusions:Genetic approaches to delete AT1aR and deplete AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. These data are consistent with ligand (AngII) dependent stimulation of AT1aR being responsible for aortic disease progression.