Coagulation factor Xa induces endothelium-dependent relaxations in rat aorta

Area of Science:

• Vascular pharmacology
• Biochemistry
• Endothelial function

Background:

• Coagulation factor Xa (FXa) is a key enzyme in hemostasis.
• The vascular effects of FXa beyond coagulation are not fully understood.
• Proteases like thrombin and trypsin can modulate vascular tone.

Purpose of the Study:

• To investigate the relaxing effect of coagulation factor Xa on phenylephrine-contracted rat aortic rings.
• To compare the mechanism of FXa-induced relaxation with that of thrombin and trypsin.
• To elucidate the specific endothelial pathways involved in FXa-mediated vasodilation.

Main Methods:

• Isolated rat aortic rings precontracted with phenylephrine.
• Dose-response studies with coagulation factor Xa, thrombin, and trypsin.
• Inhibition studies using hirudin, DX9065A (FXa inhibitor), and N omega-nitro-L-arginine methyl ester (NO synthase inhibitor).
• Desensitization experiments with thrombin and trypsin.

Main Results:

• FXa, thrombin, and trypsin induced dose-dependent relaxation in intact endothelium.
• FXa (EC50 = 16 +/- 1 nmol/L) showed slower, sustained relaxation compared to thrombin (EC50 = 3 +/- 1 nmol/L) and trypsin (EC50 = 24 +/- 9 nmol/L).
• FXa-induced relaxation was dependent on nitric oxide (NO) synthase activity and abolished by a specific FXa inhibitor (DX9065A), but not by hirudin.
• FXa relaxed thrombin-desensitized tissues but was ineffective in trypsin-desensitized tissues, suggesting a distinct receptor interaction.

Conclusions:

• Coagulation factor Xa induces vasodilation via a NO-dependent pathway.
• FXa acts on a cleavable endothelial receptor, distinct from the thrombin receptor.
• The findings suggest FXa activates a trypsin-sensitive endothelial receptor, leading to NO release and vascular relaxation.