All Phenotypes Arhgap18<tm1a(KOMP)Wtsi> MGI Mouse

cardiovascular system phenotype ( J:267328 )

N

• under basal conditions, 20-week-old male mice show normal elastin lamella architecture and vessel size in the ascending thoracic aorta and abdominal aorta by van Gieson staining

• males show normal systolic blood pressure at baseline and after angiotensin II (AngII) infusion relative to wild-type controls

abnormal aorta wall morphology ( J:267328 )

• after AngII infusion, males exhibit 2 distinct phenotypes: (i) an area with thickened media that is similar to aneurysmal aortic architecture of AngII-infused wild-type controls and (ii) an area of thin aortic media that forms a saccular shape in the aorta

abnormal aorta tunica adventitia morphology ( J:267328 )

• after AngII infusion, thoracic aortic aneurysms (TAAs) with a thin aneurysmal wall exhibit only 2 to 3 layers of elastic lamina, along with adventitial thickening

abnormal aorta tunica media morphology ( J:267328 )

• under basal conditions, the aortic media shows reduced Acta2 (actin alpha 2, smooth muscle, aorta) staining with a loss of organized actin structure in the ascending thoracic aorta

abnormal aorta elastic tissue morphology ( J:267328 )

• after AngII infusion, TAAs with a thin aneurysmal wall exhibit only 2 to 3 layers of elastic lamina, along with adventitial thickening

abnormal abdominal aorta morphology ( J:267328 )

• under basal conditions, the abdominal aorta shows reduced Acta2 staining and decreased phalloidin staining and F-actin content, indicating loss of organized cytoskeletal actin stress fibers

abnormal ascending aorta morphology ( J:267328 )

• under basal conditions, the ascending thoracic aorta shows reduced Acta2 staining and decreased phalloidin staining and F-actin content

increased susceptibility to induced aneurysm formation ( J:267328 )

• after AngII infusion for 28 days, males show severe ballooning exclusively in the ascending thoracic aorta, with no aneurysms detected in the abdominal aorta; in contrast, 27% of AngII-infused wild-type controls exhibit abdominal aortic aneurysms

• overall, >70% Ang II-infused males develop thoracic aortic aneurysms (TAAs) versus less than 30% in AngII-infused wild-type controls

• Ang II-infused males develop more severe TAAs, showing a further increase in total aortic area, a greater reduction in the media area, and more elastin breaks in the ascending thoracic aorta than AngII-infused wild-type controls

• TAAs with a thin aneurysmal wall exhibit only 2 to 3 layers of elastic lamina, along with adventitial thickening

• severe TAA formation is characterized by a further reduction in RNA expression of Acat2, along with a further increase in Mmp2 expression and a higher % of CD45+ cells indicating increased inflammatory cell infiltration

• increased TAA formation is associated with loss of Akt activation; active Akt (phosphorylated-Akt), total Akt levels, and Akt2 expression are significantly decreased at baseline and further reduced after Ang II treatment

increased susceptibility to aneurysm induced morbidity/mortality ( J:267328 )

• after AngII infusion for 28 days, 15% of mice exhibit aortic rupture and death, not observed in AngII-treated wild-type controls

abnormal vascular smooth muscle physiology ( J:267328 )

• under basal conditions, mice are phenotypically normal but exhibit a highly synthetic, proteolytic, and proinflammatory SMC phenotype in aortic tissues, with a significant decrease in RNA expression of SMC contractile markers (Myh11, Acta2, Tagln and Cnn1) along with increased expression of synthetic (Klf4, Klf5, Myh10, Opn), matrix metalloproteinases (Mmp2, -3, -9, -13 and -14), and inflammatory (Il1b, Il6, Tnf, Ccl2 and Vcam1) markers

• after AngII infusion, aneurysmal dilation in the thoracic aorta is accompanied by a further reduction in Acta2 expression, along with a further increase in Mmp2 expression and a higher % of CD45+ cells

• treatment of primary aortic SMCs with rapamycin (a mTORC1 inhibitor) can significantly reduce the level of synthetic markers and expression of key MMPs and proinflammatory genes but cannot rescue the defective contractile SMC phenotype

decreased vasoconstriction ( J:267328 )

• in vitro, isolated SMCs seeded in a polymerized collagen matrix show complete loss of contractility

• under basal conditions, thoracic and abdominal aorta tissues show a significant decrease in the expression of SMC contractile structural markers (Myh11, Acta2, Tagln and Cnn1)

• treatment of primary aortic SMCs with rapamycin fails to increase the expression of SMC contractile markers and induce Akt2 activation and expression and is thus unable to rescue the defective contractile SMC phenotype