Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice

Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCH deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCH during vascular remodeling remain elusive. To clarify the role of HCH in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII-/- mice were embryonically lethal. In HCII+/- mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII+/- mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII+/- mice. The intimal hyperplasia in HCII+/- mice with vascular injury was abrogated by human HCH supplementation. Furthermore, HCH deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCH protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCH is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.