Interferon stimulated gene 15 (ISG15) modulates phenotype of vascular smooth muscle cells and pathological vascular remodeling.

Abstract

Introduction: Inflammation is a major determinant of abdominal aortic aneurysms (AAA). Interferon stimulated gene 15 (ISG15) has a role in vascular remodelling in AAA. This study investigates the mechanisms whereby ISG15 might affect vascular remodeling and function.

Methods: We used vascular smooth muscle cells (VSMC) from wild type (ISG15^+/+) o ISG15 knockout (ISG15^-/-) mice, aorta from ISG15^+/+ and ISG15^-/- mice infused with angiotensin II (1.44mg/kg/day, sc, 14 days), and human AAA. We also performed a model of recombinant ISG15 infusion (rISG15, sc, 100 and 500ng/day, 14 days) in mice.

Results: In VSMC, ISG15 deficiency increased the expression of contractile (Acta2, Tagln) and synthetic (Fn1, Col1a2, Col3, Col4) markers and decreased the expression of the calcification marker Spp1. Ang II infusion changed the expression of phenotype markers differently in aorta from ISG15^+/+ or ISG15^-/- mice. ISG15 expression showed a negative correlation with expression of contractile markers (ACTA2, CNN1), and with COL3a1, in human samples from patients with AAA or with stenotic aorto-iliac pathology. rISG15 infusion induced hypotrophic vascular remodelling in mesenteric arteries without affecting vascular mechanics. Aorta of ISG15^-/- mice contracted more to thromboxane A₂ analogue U46619, compared to ISG15^-/-mice. Both aorta and mesenteric arteries from rISG15-treated mice showed less contractility than control mice.

Conclusions: ISG15 participates in pathological vascular remodeling probably by modulating VSMC phenotype. These changes could also impact in the vascular function.