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Updated: Aug 4, 2026

Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
08:41

Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues

Published on: June 3, 2019

FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834

K McLean1, S Schirm, A Johns

  • 1Berlex Biosciences, Richmond, CA 94804, USA. kirk_mclean@berlex.com

Thrombosis Research
|September 20, 2001
PubMed

Insights

Factor Xa (FXa), a clotting factor, triggers vascular cell signaling and proliferation, potentially worsening vascular disease. An FXa inhibitor, ZK-807834, effectively blocks these harmful cellular responses.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Vascular Biology

Background:

  • Vascular wall cells encounter clotting factors like thrombin and Factor Xa (FXa) during thrombosis.
  • Both thrombin and FXa are known to activate cell signaling pathways.
  • FXa's role in vascular cell signaling, independent of prothrombin activation, requires further elucidation.

Purpose of the Study:

  • To investigate the mechanisms by which FXa induces cell signaling in vascular wall cells.
  • To identify the specific receptors and pathways involved in FXa-mediated signaling.
  • To evaluate the potential of FXa inhibitors in mitigating FXa-induced cellular responses.

Main Methods:

  • Dose-dependent induction of intracellular Ca(2+) transients in response to FXa.
  • Assessment of FXa signaling inhibition using specific inhibitors (argatroban, hirudin, ZK-807834) and peptides.
  • Evaluation of FXa interaction with protease-activated receptors (PAR-1, PAR-2) and effector cell protease 1 receptor (EPR-1).
  • Analysis of FXa-induced cellular responses including proliferation, IL-6 production, and tissue factor expression.

Main Results:

  • FXa induces dose-dependent intracellular Ca(2+) transients in vascular wall cells.
  • FXa signaling is active-site-dependent, Gla-domain-independent, and enhanced by assembly into the prothrombinase complex.
  • Signaling is independent of prothrombin activation but completely blocked by the FXa inhibitor ZK-807834 (CI-1031).
  • FXa signaling is mediated by PAR-1 and PAR-2, not EPR-1.
  • FXa promotes cell proliferation, IL-6 production, and tissue factor expression.
  • These FXa-induced responses are inhibited by ZK-807834.

Conclusions:

  • FXa activates vascular cell signaling through PAR-1 and PAR-2, independent of prothrombin activation.
  • FXa induces pathophysiological responses including proliferation and cytokine/tissue factor production.
  • The FXa inhibitor ZK-807834 effectively blocks FXa-mediated signaling and associated cellular responses.
  • Targeting FXa signaling may offer a therapeutic strategy for vascular diseases.

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