Ryan M. McEnaney, MD, Ankur Shukla, MD, Michael C

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P2Y2 nucleotide receptor mediates arteriogenesis in a murine model of hind limb ischemia Ryan M. McEnaney, MD, Ankur Shukla, MD, Michael C. Madigan, MD, Ulka Sachdev, MD, Edith Tzeng, MD Journal of Vascular Surgery Volume 63, Issue 1, Pages 216-225 (January 2016) DOI: 10.1016/j.jvs.2014.06.112 Copyright © 2016 Terms and Conditions

Fig 1 P2Y2−/− mice have blunted perfusion recovery and develop ischemic wounds after hind limb ischemia. A, Representative laser Doppler perfusion imaging (LPDI) at days 0 and 28 after right femoral artery ligation (FAL) in wild-type (WT) and P2Y2−/− mice. B, Perfusion was calculated from the LDPI of the plantar foot immediately after ligation and at 3, 7, 14, 21, and 28 days. Perfusion was expressed as a ratio of the right (R) ischemic/left (L) nonischemic limbs (n = 8 animals/group). Data are shown as mean ± standard error of the mean (error bars). Significant differences were observed between groups from day 14 through day 28 (one-way analysis of variance). *P < .001 vs all other groups. C, Representative photographs of the ischemic foot at day 14 demonstrate gangrene and tissue loss in the P2Y2−/− mouse. Gangrene developed in the ischemic foot of 50% (n = 4 of 8) of the P2Y2−/− animals. Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 2 P2Y2−/− mice exhibited increased inflammation and muscle regeneration in the ischemic hind limb compared with wild-type (WT) mice. A, Representative photomicrographs of tibialis anterior (TA) muscle stained with anti-cluster of differentiation (CD) 45 (red) and 4,′6-diamidino-2-phenylindole dihydrochloride (DAPI; blue) at original magnification ×60. B, Representative photomicrograph of TA muscle stained with hematoxylin and eosin (H&E). WT mice exhibited normal muscle architecture and normally appearing mature myocytes with peripheral nuclei (arrowhead). Muscle from P2Y2−/− mice had a high predominance of regenerating myocytes that are characterized by centralized nuclei (arrow; n = 4 per group; three sections were analyzed per animal). C, CD45+ cells were counted and expressed as number per high-power field. Significantly more CD45+ cells were identified in the P2Y2−/− ischemic muscles than in the WT muscle (n = 4 per group; three sections were analyzed per animal). *P < .001 vs all other groups. Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 3 Angiogenesis was increased in P2Y2−/− mice after femoral artery ligation. Tibialis anterior (TA) muscles from wild-type (WT) and P2Y2−/− mice were sectioned and stained at 28 days after hind limb ischemia. Endothelial cell (EC) and capillary structures were stained with anticluster of differentiation (CD)31. A, Representative confocal photomicrographs of TA muscle sections stained with anti-CD31 (green) and 4,′6-diamidino-2-phenylindole dihydrochloride (DAPI; blue) and imaged at original magnification ×60. B, CD31+ structures were counted and expressed as a ratio to number of total myocytes per section (n = 4 per group; four sections per animal). ∗P < .05. The error bars show the standard error of the mean. Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 4 Proliferative activity in the collateral vessels was increased in wild-type (WT) mice compared with P2Y2−/− mice. Collateral vessels were examined 3 days after femoral artery ligation (FAL). Tissue sections were stained for Ki67 (red), cluster of differentiation (CD)31 (green), and 4,′6-diamidino-2-phenylindole dihydrochloride (DAPI; blue). A, Representative confocal photomicrographs are shown at original magnification ×100. B, Quantification of Ki67+ cells in the collateral vessels, expressed as the percentage total number of perivascular cells (n = 5 mice per group; three sections were analyzed per animal). *P < .001 vs all other groups. The error bars show the standard error of the mean. Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 5 Vascular cell adhesion molecule (VCAM-1) expression in collateral vessels after hind limb ischemia was increased in wild-type (WT) vs P2Y2−/− mice. Sections of muscle isolated 3 days after femoral artery ligation (FAL) were stained for VCAM-1 (red) and α-smooth muscle actin (green), and with 4,′6-diamidino-2-phenylindole dihydrochloride (DAPI; blue). Collateral vessels were imaged by confocal microscopy at original magnification ×100. Representative images are shown for WT and P2Y2−/− animals. Endotheli−/−al staining for VCAM-1 was seen in the collateral vessels from WT mice (arrow) but not the P2Y2−/− mice (n = 5 mice per group; three sections were analyzed per animal). Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 6 Representative photographs of Microfil (Flow Tech Inc, Carver, Mass) casting of the hind limb arterial system are shown. Animals were casted at 28 days after femoral artery ligation (FAL). Collateral vessels are noted by arrows showing similar distributions between wild-type (WT) and P2Y2−/− mice but less robust development in the P2Y2−/− mice (quantification is summarized in the Table; n = 4 mice per group). Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions

Fig 7 Early inflammation was reduced in the ischemic hind limb from P2Y2−/− mice compared with wild-type (WT) mice at 7 days after femoral artery ligation (FAL). However, myocyte necrosis was increased in the P2Y2−/− mice. A, Representative photomicrographs are shown at original magnification ×20 and demonstrate F4/80 (macrophages, yellow) and 4,′6-diamidino-2-phenylindole dihydrochloride (DAPI; blue) staining of WT and P2Y2−/− hind limb muscle at day 7. Myocyte necrosis is denoted by vacuolated cells (solid white arrow), whereas regenerating myocytes have centrally located nuclei (open arrow; n = 4-5 mice/group; three sections per animal). B, Quantification of macrophage infiltration is reported as number of macrophages/total myocyte per high-powered field and expressed as percentage, with mean data presented with the standard error of the mean (error bars). C, Quantification of myocyte necrosis is reported as number of necrotic myocyte/total myocyte per high-powered field. D, Quantification of regenerating myocyte is reported as number of regenerating myocyte/total myocyte per high-powered field (n = 4-5 mice per group; three sections per animal). *P > .05. Journal of Vascular Surgery 2016 63, 216-225DOI: (10.1016/j.jvs.2014.06.112) Copyright © 2016 Terms and Conditions