Seipelt Ralf G, Backer Carl L, Mavroudis Constantine, Stellmach Veronica, Cornwell Mona, Seipelt Ingrid M, Schoendube Friedrich A, Crawford Susan E
Department of Surgey, Children's Memorial Hospital, Northwestern Univeristy Feinberg School of Medicine, Chicago, IL 60614, USA.
J Thorac Cardiovasc Surg. 2005 Aug;130(2):355-62. doi: 10.1016/j.jtcvs.2004.12.040.
Vascular remodeling, often accelerated after cardiovascular procedures, may result in stenosis or aneurysm formation. The bone-associated protein osteopontin has been suggested to be involved in vascular remodeling, yet the effect of locally applied osteopontin in an acute vascular injury model of aortic calcification has not been examined.
Vascular healing of rabbit thoracic aortas treated locally with recombinant osteopontin (dose: 1 microg; n = 16) or albumin (control, n = 16) after acute injury created by end-to-end anastomosis was evaluated. Matrix metalloproteinase-2 level was quantified by gelatin zymography. Proliferation of smooth muscle cells was detected by immunostaining for proliferative cell nuclear antigen.
Osteopontin-treated aortas showed significantly diminished vascular remodeling with less calcification (P = .001) and reduced anastomotic luminal stenosis (4% vs 28%, P = .002) compared with controls 2 months postsurgery. Moreover, osteopontin-treated aortas revealed a thickened adventitia with increased fibrosis (P = .006). Matrix metalloproteinase-2 level was up-regulated 2-fold with osteopontin treatment compared with control at 1 week, returning to baseline by 1 month. Staining for proliferation cell nuclear antigen disclosed an increase in proliferation cell nuclear antigen-positive smooth muscle cells in the media of osteopontin-treated aortas at 1 week, normalizing by 1 month.
These data suggest a beneficial effect of locally applied osteopontin after acute injury possibly by altering matrix metalloproteinase-2 activity and smooth muscle cell proliferation. Brief application of osteopontin may effectively enhance vascular healing by reducing calcification and thus maintaining luminal integrity. The role of the osteopontin-related increase in adventitial fibrosis on vascular healing has to be explored.
血管重塑在心血管手术后常加速进行，可能导致狭窄或动脉瘤形成。有研究表明，骨相关蛋白骨桥蛋白参与血管重塑，但局部应用骨桥蛋白在主动脉钙化急性血管损伤模型中的作用尚未得到研究。
对兔胸主动脉进行端端吻合造成急性损伤后，局部用重组骨桥蛋白（剂量：1微克；n = 16）或白蛋白（对照组，n = 16）处理，评估血管愈合情况。通过明胶酶谱法对基质金属蛋白酶-2水平进行定量。通过增殖细胞核抗原免疫染色检测平滑肌细胞增殖情况。
与对照组相比，术后2个月，骨桥蛋白处理的主动脉显示血管重塑明显减轻，钙化减少（P = .001），吻合口管腔狭窄减轻（4% 对 28%，P = .002）。此外，骨桥蛋白处理的主动脉外膜增厚，纤维化增加（P = .006）。与对照组相比，骨桥蛋白处理1周后基质金属蛋白酶-2水平上调2倍，1个月后恢复至基线水平。增殖细胞核抗原染色显示，骨桥蛋白处理的主动脉中膜增殖细胞核抗原阳性平滑肌细胞在1周时增加，1个月时恢复正常。
这些数据表明，急性损伤后局部应用骨桥蛋白可能通过改变基质金属蛋白酶-2活性和平滑肌细胞增殖产生有益作用。短暂应用骨桥蛋白可通过减少钙化从而维持管腔完整性有效促进血管愈合。骨桥蛋白相关的外膜纤维化增加对血管愈合的作用有待进一步探索。
