Abstract 17361: Loss of Notch1 in the Secondary Heart Field Exacerbates Ascending Aortic Aneurysm and Causes Aortic Rupture in Marfan Syndrome Mice (Best of Basic Science Abstract)

Abstract

Ascending aortic aneurysm (AscAA) is a life-threatening disease that affects approximately 3.5 in 100,000 people per year, but the mechanisms of AscAA remain poorly understood. We previously reported that NOTCH1 mutations are associated with familial bicuspid aortic valve (BAV), and a subset of these individuals displayed BAV aortopathy. NOTCH1 is expressed in multiple cell lineages that contribute to the aorta, and we found dysregulation of activated NOTCH1 expression in aneurysmal tissue from Marfan syndrome and BAV patients in comparison to control tissue. To investigate the role of NOTCH1 in AscAA, Notch1 haploinsufficiency was introduced into the Marfan syndrome mouse ( Fbn1 C1039G/+ ), a well-described model of AscAA. Serial echocardiographic, gross and histological characterization of the Notch1 deficient Marfan syndrome mice ( Notch1 +/- ;Fbn C1039G/+ ) demonstrated an exacerbated AscAA phenotype when compared to Fbn1 C1039G/+ mice. The compound mutant mice had increased aortic root diameter by three months of age (diameter: Notch1 +/- ;Fbn C1039G/+ = 2.11±0.11mm and Fbn1 C1039G/+ = 1.86±0.05mm, p<0.05) as well as a higher rate of dilation from 1-5 months of age (rate: Notch1 +/- ;Fbn C1039G/+ =0.24±0.06mm/month and Fbn1 C1039G/+ =0.09±0.03mm/month, p<0.05). Notch1 +/- and wildtype littermate mice had normal aortic diameters. Furthermore, a small subset (4/66) of the compound mutant mice succumbed to ascending aortic rupture, which was not observed in the Fbn1 C1039G/+ mice (0/63). Although endothelial Notch1 is critical for cardiovascular development, mice with heterozygous loss of Notch1 in endothelial cells that harbor the Fbn1 C1039G mutation ( Notch1 flox/+ ;Tie2-Cre +/- ;Fbn1 C1039G/+ ) did not recapitulate the phenotype of the Notch1 +/- ;Fbn C1039G/+ mice. Surprisingly, the phenotype was recapitulated with heterozygous loss of Notch1 in the lineage of secondary heart field cells ( Notch1 flox/+ ;Mef2C-AHF-Cre +/- ;Fbn1 C1039G/+ ) but not smooth muscle myosin heavy chain-expressing cells ( Notch1 flox/+ ;Myh11-Cre +/- ;Fbn1 C1039G/+ ). Our findings support a novel role for Notch1 in the non-endothelial secondary heart field and suggest that this loss of Notch1 alters a developmental process that contributes to AscAA.