The remodeling of the extracellular matrix plays a vital role in cardiovascular diseases (CVDs). Utilising a mouse model of postnatal ascending aortic aneurysms, it has been reported that abnormal mechanosensing led to aneurysm formation Fbln4SMKO with an upregulation of the mechanosensitive transcription factor, Egr1 (Early growth response 1). However, the role of Egr1 and its upstream regulator(s) in the initiation of aneurysm development and their relationship to an aneurysmal microenvironment is unknown.
This study aimed to investigate the contribution of Egr1 in the aneurysm development. Egr1 in Fbln4SMKO mice and generated double knockout mice (DKO, Fbln4SMKO; Egr1−/−) were deleted. Aneurysms were prevented in DKO mice (42.8%) and Fbln4SMKO; Egr1+/− mice (26%). Transcript and protein levels of PAR1 were greatly elevated in Fbln4SMKO aortas at postnatal day one before aneurysm formed, together with MMP (matrix metalloproteinase)-9 and active thrombin, both of which served as PAR1 activator. The protein levels of thrombin, Egr1, and PAR1 were observed to be elevated in human thoracic aortic aneurysms. Thrombin was enough for the induction of Egr1 expression in a PAR1-dependent procedure.
In conclusion, this study proposes that MMP-9, thrombin, and mechanical stimuli in the Fbln4SMKO aorta activate PAR1, leading to the initiation of ascending aortic aneurysms by the upregulation of Egr1.