Vasostatin-2 attenuates injury-induced neointimal hyperplasia through the ACE2/MasR/PPARγ/NR1D1/Gas1 axis

Abstract Aims Vasostatin-2, a bioactive peptide derived from chromogranin A, has cardiovascular-protective and anti-inflammatory properties. However, its role in injury-induced vascular remodelling remains unclear. This study aimed to investigate whether serum vasostatin-2 levels are related to restenosis in patients following percutaneous coronary intervention (PCI), and whether this peptide influences vascular neointimal hyperplasia in a mouse model of femoral artery injury. Methods and results Serum vasostatin-2 levels were evaluated in patients with (n = 442) and without (n = 442) restenosis after PCI. Recombinant vasostatin-2 or saline was administered in a mouse model of femoral artery injury. A combination of multi-omics (Bulk RNA sequencing, CUT&Tag detection, and glutathione S-transferase pull-down/mass spectrometry analysis) was employed to investigate underlying mechanisms. Patients with restenosis had lower serum vasostatin-2 levels than those without restenosis (P < 0.001). Vasostatin-2 protein significantly inhibited neointimal hyperplasia and suppressed the vascular smooth muscle cell (VSMC) phenotype switch after injury. Mechanistically, vasostatin-2 was proven to bind angiotensin-converting enzyme 2 (ACE2) and activate the downstream nuclear receptor subfamily 1 group D member 1 (NR1D1)-growth arrest-specific 1 (Gas1) pathway, thereby facilitating apoptosis of VSMCs and inhibiting their proliferation. ACE2-binding incompetent vasostatin-2 mutants and NR1D1 deficiency in VSMCs weakened vasostatin-2 effect on neointimal hyperplasia in mice. Conclusion Decreased serum vasostatin-2 levels are associated with coronary artery restenosis in patients with coronary angioplasty. Vasostatin-2 attenuates vascular injury-induced neointimal growth in mice and inhibits the proliferation of VSMCs in vitro through the ACE2/NR1D1/Gas1 pathway.