title: Hirudin promotes angiogenesis by modulating the cross-talk between p38 MAPK and ERK in rat ischemic skin flap tissue.
abstract: Hirudin's ability to increase angiogenesis in ischemic flap tissue and improve the flaps survival has been demonstrated in our previous studies. However, the knowledge about hirudin functional role in angiogenesis is still limited. In the present study, we investigate the effects of locally injected hirudin on the expression of VEGF, endostatin and thrombospondin-1 (TSP-1) using rat model. Caudally based dorsal skin flaps were created and were treated with hirudin or normal saline. Result showed that the flap survival was improved by hirudin treatment relative to the control. Treatment of flaps with hirudin exerted significant angiogenic effect as evidenced by increased VEGF expression and reduced endostatin and TSP-1 production (p<0.01), and promoted neovascularization (microvascular density, p<0.01). Moreover, hirudin treatment increased the ERK1/2 phosphorylation, while attenuated the phosphorylation of p38 MAPK, and the addition of thrombin could reverse these effects of hirudin on ERK1/2 and p38 MAPK activity. The MEK inhibitor blocked the hirudin-induced VEGF expression, and the p38 MAPK inhibitor attenuated the thrombin-induced TSP-1 expression. Furthermore, a specific inhibitor of p38 MAPK activates ERK1/2 in ischemic flaps, suggesting that cross-talk between p38 MAPK and ERK might exist in rat ischemic flap tissue. Moreover, either the hirudin or SCH79797 (PAR1 antagonist) could attenuate the p38 MAPK phosphorylation and increases the ERK1/2 phosphorylation, indicating that the cross-talk between p38 MAPK and ERK1/2 modulated by thrombin/PAR1 signaling may participate in the process of hirudin-stimulated ERK1/2 signaling. In conclusion, these observations suggest that hirudin exerts its angiogenesis effect by regulating the expression of angiogenic and antiangiogenic factors via a cross-talk of p38 MAPK-ERK pathway.
authors.affiliation: Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China. Electronic address: seanpun@163.com.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Pan
authors.affiliation: Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China. Electronic address: pliu1979@163.com.
authors.forename: Liu
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China. Electronic address: 986832130@qq.com.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Han
authors.affiliation: Department of Plastic and Aesthetic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People's Republic of China. Electronic address: gxyingq61@163.com.
authors.forename: Guo-Qian
authors.initials: GQ
authors.lastname: Yin
authors.affiliation: Nanning JinXueHuang Bioengineering Co., Ltd., Nanning 530001, Guangxi, People's Republic of China. Electronic address: yankunsong@163.com.
authors.forename: Yan-Kun
authors.initials: YK
authors.lastname: Song
authors.affiliation: Nanning JinXueHuang Bioengineering Co., Ltd., Nanning 530001, Guangxi, People's Republic of China. Electronic address: junhuangnn@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D043169:Endostatins / Q000096:biosynthesis* / Q000235:genetics; D006629:Hirudins / Q000008:administration & dosage*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D064827:Myocutaneous Flap / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000473:pathology; D019699:Thrombospondins / Q000096:biosynthesis* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D043169:Endostatins; D006629:Hirudins; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Angiogenesis; Cross-talk of p38 MAPK/ERK; Hirudin; Ischemic flap tissue; Thrombin