title: Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade.
abstract: OBJECTIVE
  Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model.
  
  
  RESULTS
  Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation and thickening of the medial and adventitial layers of the aorta. There was significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density attributable to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC-induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC-induced adventitial hyperplasia, collagen accumulation, and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas were effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked extracellular signal-regulated kinase activation and reactive oxygen species production in the TAC ascending aorta.
  
  
  CONCLUSIONS
  Inhibition of the angiotensin II type 1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased transforming growth factor-β1 expression, adventitial Smad2 signaling, and collagen accumulation. These results help to delineate the aortic transforming growth factor-β signaling that is dependent and independent of the angiotensin II type 1 receptor after TAC.
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, University of Texas Medical Branch, Houston, TX 77030, USA.
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Kuang
authors.forename: Liang
authors.initials: L
authors.lastname: Geng
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Prakash
authors.forename: Jiu-Mei
authors.initials: JM
authors.lastname: Cao
authors.forename: Steven
authors.initials: S
authors.lastname: Guo
authors.forename: Carlos
authors.initials: C
authors.lastname: Villamizar
authors.forename: Callie S
authors.initials: CS
authors.lastname: Kwartler
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Peters
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D062186:Arterial Pressure; D001696:Biomechanical Phenomena; D003094:Collagen / Q000378:metabolism; D003250:Constriction; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen; D019808:Losartan
keywords: aortic aneurysm, thoracic; receptor, angiotensin, type 1; transforming growth factors