Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

Rationale: Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated. Objective: The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. Methods and Results: We used a mouse model of postnatal ascending aortic aneurysms (Fbln4SMKO; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulat...