Phosphorylated NPY1R regulates phenotypic transition of vascular smooth muscle cells, inflammatory response and macrophage infiltration to promote intracranial aneurysm progression.

Background: Rupture of intracranial aneurysm (IA) could give rise to spontaneous subarachnoid hemorrhage, leading to a high disability rate and even death. NPY1R expression was upregulated in aneurysm tissues of IA patients. However, the role and underlying mechanism of NPY1R remains unknown.

Methods: The IA model of mice was established using inducing systemic hypertension and injecting elastase. The expression of genes and proteins was detected by RT-qPCR and western blot. The number of T cells, macrophages, and neutrophils in IA mice was detected using flow cytometry and IF assay. The levels of inflammatory factors were measured using ELISA. Patho-morphology and inflammatory cells in aneurysm tissues were evaluated by HE staining. The interaction between TK and NPY1R was validated using Co-IP.

Results: NPY1R expression was greatly elevated in aneurysm tissues in IA patients and mice, which were positively related to macrophage infiltration. Besides, exogenous overexpression of NPY1R resulted in the promotion of contractile phenotype to the synthetic phenotype of vascular smooth muscle cells (VSMCs), inflammatory response and M1 macrophage polarization. In terms of the underlying mechanism, NPY1R protein could be modified by TK-mediated phosphorylation and TKI could decrease IA formation and suppresse contractile phenotype to synthetic phenotype of VSMCs, inflammatory response and M1 macrophage polarization in IA mice. Furthermore, ablating mouse macrophages abolished NPY1R overexpression-mediated promotion of IA formation and rupture in mice.

Conclusion: Phosphorylated NPY1R contributed to IA progression through promoting contractile phenotype to synthetic phenotype of VSMCs, inflammatory response and M1 macrophage polarization in IA.