Abstract
AimsIn 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 ResultsPAR1-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.ConclusionPAR2, 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.
Highlights
Cardiovascular disease is one of the world’s leading causes of mortality
We address the physiological relevance of PAR1 and PAR2 in arteriogenesis in a hind limb ischemia model using mice deficient in either of these receptors
In addition to the capillary staining, we found reduced sprout formation in PAR2-/- aortas when compared to WT aortas in an ex vivo aortic sprouting assay (Supplementary material online, Figure S3), indicating that impaired angiogenesis is a general phenomenon in PAR2-/- mice that is independent of arteriogenesis
Summary
Cardiovascular disease is one of the world’s leading causes of mortality. Occlusion of coronary arteries or large peripheral arteries, as a consequence of an atherosclerotic lesion or thrombus, causes insufficient blood supply to the heart or lower extremities. In response to the resulting increased shear flow, the interconnecting arterioles between the large vessels remodel into mature collaterals, a process referred to as arteriogenesis [1]. Risk factors related to diabetes or hyperlipidaemia impair this compensatory mechanism [2]. At the onset of arteriogenesis, increased shear stress against the inner arteriolar wall facilitates endothelium-dependent attraction, adhesion and extravasation of circulating monocytes toward the pre-existing arterioles. Monocytes differentiate into macrophages followed by secretion of a variety of arteriogenic cytokines, including vascular growth factors, matrix-degrading proteases and chemo-attractants, which support collateral maturation [3]
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