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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors: Lisa G
authors: LG
authors: van den Hengel
authors: Alwine A
authors: AA
authors: Hellingman
authors: Anne Yael
authors: AY
authors: Nossent
authors: Annemarie M
authors: AM
authors: van Oeveren-Rietdijk
authors: Margreet R
authors: MR
authors: de Vries
authors: C Arnold
authors: CA
authors: Spek
authors: Anton Jan
authors: AJ
authors: van Zonneveld
authors: Pieter H
authors: PH
authors: Reitsma
authors: Jaap F
authors: JF
authors: Hamming
authors: Hetty C
authors: HC
authors: de Boer
authors: Henri H
authors: HH
authors: Versteeg
authors: Paul H A
authors: PH
authors: Quax
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology; D002454:Cell Differentiation; D003097:Collateral Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D005263:Femoral Artery; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia; D037181:Lectins, C-Type / Q000276:immunology; D008026:Ligation; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000276:immunology
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface
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