Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model

Background: Investigations in factor VII activating protease (FSAP)(-/-) mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. Methods and results: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP(-/-) mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP(-/-) mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP(-/-) mice. Conclusions: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP.