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- Title
Protease-Activated Receptor (PAR)2, but Not PAR1, Is Involved in Collateral Formation and Anti-Inflammatory Monocyte Polarization in a Mouse Hind Limb Ischemia Model.
- Authors
van den Hengel, Lisa G.; Hellingman, Alwine A.; Nossent, Anne Yael; van Oeveren-Rietdijk, Annemarie M.; de Vries, Margreet R.; Spek, C. Arnold; van Zonneveld, Anton Jan; Reitsma, Pieter H.; Hamming, Jaap F.; de Boer, Hetty C.; Versteeg, Henri H.; Quax, Paul H. A.
- Abstract
Aims: In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. Methods and Results: PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. Conclusion: PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients.
- Subjects
PROTEASE-activated receptors; COLLATERAL circulation; ANTI-inflammatory agents; MONOCYTES; ISCHEMIA treatment; CELLULAR signal transduction; MYOCARDIAL infarction; G proteins; LABORATORY mice
- Publication
PLoS ONE, 2013, Vol 8, Issue 4, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0061923