Integrin αV emerges as a potential therapeutic target with cautionary implications in thoracic aortic aneurysm and dissection.

OBJECTIVE

Thoracic aortic aneurysm (TAA) is a life-threatening condition that predisposes to aortic dissection (AD), yet its underlying pathophysiologic mechanisms remain poorly understood.

METHODS

Tandem mass tag-based quantitative proteomics of plasma from type A AD patients was performed to identify dysregulated proteins. The β-aminopropionitrile-induced mouse model was used to experimentally recapitulate TAA progression, with disease mechanisms further characterized through RNA sequencing transcriptomics, complemented by comprehensive molecular analyses including immunohistochemistry, immunofluorescence, western blot, co-immunoprecipitation, and bioinformatics integration.

RESULTS

Integrin αV and integrin αL were significantly downregulated proteins in plasma samples from patients with type A AD. Integrin αV abundantly expressed in the aortic media, particularly in smooth muscle cells (SMCs), with significantly reduced expression after dissection. Pharmacologic inhibition of integrin αV with cilengitide or SB273005 markedly aggravated ascending TAA development, accompanied by severe disorganization and loss of elastic fibers. Bulk RNA sequencing revealed that integrin αV inhibition exacerbated proinflammatory responses during TAA progression. Inhibiting integrin αV disrupted the SMC transition to a contractile phenotype, whereas STAT1 negatively regulated integrin αV-mediated SMC phenotypic modulation.

CONCLUSIONS

These findings identify integrin αV as a promising molecular target for TAA intervention. However, they also highlight concerns regarding the clinical use of integrin αV inhibitors, which are currently under investigation in cancer trials because they may increase the risk of TAA or AD development.