Thrombin promotes arteriogenesis and hemodynamic recovery in a rabbit hindlimb ischemia model

Κατσάνος, Κωνσταντίνος; Karnabatidis, Dimitrios; Diamantopoulos, Athanasios; Kagadis, George C.; Ravazoula, Panagiota; Nikiforidis, George; Siablis, Dimitrios; Tsopanoglou, Nikos E.

doi:10.1016/j.jvs.2008.11.004

Cited by 20 publications

(24 citation statements)

References 45 publications

(49 reference statements)

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“…Administration of thrombin, trypsin or a PAR2-derived synthetic peptide enhances blood flow recovery, but only for thrombin it is known that it increases collateral formation after induction of hind limb ischemia by excision of the femoral artery [19], [20]. While in these studies collateral formation was dependent on supraphysiological concentrations of the PAR1-agonist thrombin and detailed data on collateralization upon PAR2 activation is missing, direct evidence for a physiological role of PAR1 and PAR2 in collateral formation is still lacking.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…Arteriogenesis is essential to the re-establishment of an adequate blood supply to ischemic organs and tissues. It was previously thought that compared to angiogenesis (capillary formation), arteriogenesis is a distinct process based on the remodeling and maturation of pre-existing arterioles and arteries, 1) characterized by proliferation of pre-existing smooth muscle cells (SMCs), endothelial cells (ECs), or their resident precursors. 2) Recent reports that arteriogenesis is augmented by bone marrow mononuclear cells [3][4][5] and endothelial progenitor cells suggest involvement in arteriogenesis of not only proliferation of resident cells, but also migration and proliferation of circulating stem cells/precursor cells.…”

mentioning

confidence: 99%

Migration of Mononuclear Cells Expressing β-Actin Through the Adventitia into Media and Intima in Coronary Arteriogenesis and Venogenesis in Ischemic Myocardium

Uchida

Maezawa

et al. 2012

Int. Heart J.

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SummaryIt was previously thought that arteriogenesis and venogenesis are induced not only by proliferation of vessel-resident smooth muscle cells (SMCs) and endothelial cells (ECs) but also by migration of their precursors. However, it is not well understood through what route(s) the precursors migrate into the existing vessels.We examined through what route or routes circulating mononuclear cells expressing β-actin (β-MNCs), which we identified in canine coronary vessels, migrate into coronary vessel walls and cause arteriogenesis and venogenesis at 1, 2, 4 and 8 weeks after induction of myocardial infarction.The following changes were observed: (1) The β-MNCs migrated via coronary microvessels to the interstitial space at one week; (2) β-MNCs traversed the adventitia into the media and settled in parallel with pre-existing smooth muscle cells (SMCs) in arterioles and arteries and lost β-actin and acquired α-smooth muscle actin (α-SMA) to become mature SMCs at 2-4 weeks; (3) at the same time, other β-MNCs migrated across the adventitia and media into the intima and settled in parallel with pre-existing endothelial cells (ECs) and lost β-actin, while acquiring CD 31 , to become mature ECs, resulting in arteriogenesis; (4) Similarly, β-MNCs migrated into venular and venous walls and became SMCs or ECs, resulting in venogenesis.β-MNCs in the interstitial space expressed CD 34 but not other major vascular cell markers. β-MNCs, possibly a vascular progenitor, migrate not from the lumen but across the adventitia into the media or intima of coronary vessels and transit to SMCs or ECs, and participate in arteriogenesis and venogenesis in ischemic myocardium. (Int Heart J 2012; 53: 54-63)

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“…Several studies have demonstrated arterogenisis as the dominant mode of native vascular remodeling in young otherwise healthy subjects. [23][24][25] Of note, extensive collateralization was seen on arteriography in animals subjected to ligation in this study, which undoubtedly contributed to recovery after a vascular injury. This observation corroborates findings by others who have described decreasing collateral resistance 2 weeks after femoral artery occlusion in pigs.…”

Section: Figmentioning

confidence: 50%

The impact of ischemic intervals on neuromuscular recovery in a porcine (Sus scrofa) survival model of extremity vascular injury

Burkhardt

Gifford

Propper

et al. 2011

Journal of Vascular Surgery

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In this model, surgical and therapeutic adjuncts to restore extremity perfusion early (1-3 hours) after extremity vascular injury are most likely to provide outcomes benefit compared with delayed restoration of flow or ligation. Furthermore, the ischemic threshold of the extremity after which neuromuscular recovery is significantly diminished is less than 5 hours. Additional studies are necessary to determine the effect of other factors such as shock or therapeutic measures on this ischemic threshold.

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Thrombin promotes arteriogenesis and hemodynamic recovery in a rabbit hindlimb ischemia model

Cited by 20 publications

References 45 publications

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

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

Migration of Mononuclear Cells Expressing β-Actin Through the Adventitia into Media and Intima in Coronary Arteriogenesis and Venogenesis in Ischemic Myocardium

The impact of ischemic intervals on neuromuscular recovery in a porcine (Sus scrofa) survival model of extremity vascular injury

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