Nerve Growth Factor Promotes Angiogenesis and Skeletal Muscle Fiber Remodeling in A Mouse Hindlimb Ischemic Model_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 DIAOYong-peng ¹ , GUOLi-long ¹ , LIANLi-shan ¹ , YANSheng ¹ , CHENHou-zao ² ,  LIYong-jun ¹

1. Department of Vascular Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China;
2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China;

Corresponding author：

LIYong-jun, Email: yongj_93@hotmail.com

Keywords：

Limb ischemia; Angiogenesis; Nerve growth factor; Vascular endothelial growth factor; Muscle fiber type

DOI：

10.7507/1007-9424.20150045

Video：

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Objective To evaluate the effects of nerve growth factor (NGF) on angiogenesis and skeletal muscle fiber remodeling in ischemic hindlimbs, and study the relationship of NGF and vascular endothelial growth factor (VEGF) to angiogenesis. Methods Eighteen mice were randomly allocated to normal control group (n=6), blank control group (n=6), and NGF gene transfection group (n=6). The left hindlimb ischemia model was established by ligating the femoral artery. NGF plasmid (125μg) was injected into the mouse ischemic gastrocnemius in the NGF gene transfection group. The same volume of normal saline (200μL) was injected into the mouse ischemic gastrocnemius in the blank control group. The gastrocnemius of left hindlimb was harvested under the condition of peritoneal cavity anesthesia on the 21th day after operation, and then the mice were sacrificed. The gastrocnemius of three groups were tested by hematoxylin-eosin staining, proliferating cell nuclear antigen (PCNA) and CD34 were determined by immunohistochemistry staining. Skeletal muscle fiber type was tested by myosin ATPase staining. NGF and VEGF protein expression were detected by enzyme linked immunosorbent assay. Results On the 21th day after surgery, compared with the blank control group, the skeletal muscle atrophy degree was weaker, the functional assessment score was significantly lower (P < 0.05), the endothelial cell proliferation index, capillary density, the typeⅠskeletal muscle fiber proportion, NGF and VEGF expression were significantly higher (P < 0.05) in the NGF gene transfection group. Conclusions NGF gene transfection could promote NGF and VEGF expression and angiogenesis in ischemic hindlimbs, and induce typeⅠskeletal muscle fibers formation in ischemic hindlimbs. The molecular regulation mechanism still needs to be further studied.

Citation： DIAOYong-peng, GUOLi-long, LIANLi-shan, YANSheng, CHENHou-zao, LIYong-jun. Nerve Growth Factor Promotes Angiogenesis and Skeletal Muscle Fiber Remodeling in A Mouse Hindlimb Ischemic Model. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(2): 166-170. doi: 10.7507/1007-9424.20150045 Copy

1.	Emanueli C, Salis MB, Milia AF, et al. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Hypertension, 2002, 40(3): 402.
2.	Karatzas A, Katsanos K, Lilis I, et al. NGF promotes hemodynamic recovery in a rabbit hindlimb ischemic model through trkA-and VEGFR2-dependent pathways. J Cardiovasc Pharmacol, 2013, 62(3): 270-277.
3.	Katare R, Stroemer P, Hicks C, et al. Clinical-grade human neural stem cells promote reparative neovascularization in mouse models of hindlimb ischemia. Arterioscler Thromb Vasc Biol, 2014, 34(2): 408-418.
4.	Stabile E, Burnett MS, Watkins C, et al. Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice. Circulation, 2003, 108(2): 205-210.
5.	Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals, 2005, 14(5): 207-221.
6.	Renault MA, Chapouly C, Yao Q, et al. Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival. Circ Res, 2013, 112(5): 762-770.
7.	Jadhao CS, Bhatwadekar AD, Jiang Y, et al. Nerve growth factor promotes endothelial progenitor cell-mediated angiogenic responses. Invest Ophthalmol Vis Sci, 2012, 53(4): 2030-2037.
8.	Liu X, Li Y, Liu Y, et al. Endothelial progenitor cells (EPCs) mobilized and activated by neurotrophic factors may contribute to pathologic neovascularization in diabetic retinopathy. Am J Pathol, 2010, 176(1): 504-515.
9.	Steinle JJ, Granger HJ. Nerve growth factor regulates human choroidal, but not retinal, endothelial cell migration and proliferation. Auton Neurosci, 2003, 108(1/2): 57-62.
10.	Romon R, Adriaenssens E, Lagadec C, et al. Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Mol Cancer, 2010, 9: 157.
11.	Trapani L, Melli L, Segatto M, et al. Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions. FASEB J, 2011, 25(11): 4037-4047.
12.	Bloemink MJ, Adamek N, Reggiani C, et al. Kinetic analysis of the slow skeletal myosin MHC-1 isoform from bovine masseter muscle. J Mol Biol, 2007, 373(5): 1184-1197.
13.	Schiaffino S, Reggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev, 1996, 76(2): 371-423.
14.	Furrer R, De Haan A, Bravenboer N, et al. Effects of concurrent training on oxidative capacity in rat gastrocnemius muscle. Med Sci Sports Exerc, 2013, 45(9): 1674-1683.
15.	Matsakas A, Yadav V, Lorca S, et al. Revascularization of ischemic skeletal muscle by estrogen-related receptor-gamma. Circ Res, 2012, 110(8): 1087-1096.
16.	Chakkalakal JV, Kuang S, Buffelli M, et al. Mouse transgenic lines that selectively label typeⅠ, typeⅡA, and typesⅡX+B skeletal muscle fibers. Genesis, 2012, 50(1): 50-58.
17.	Sillen MJ, Franssen FM, Gosker HR, et al. Metabolic and structural changes in lower-limb skeletal muscle following neuromuscular electrical stimulation: a systematic review. PLoS One, 2013, 8(9): e69391.
18.	McGuigan MR, Bronks R, Newton RU, et al. Muscle fiber characteristics in patients with peripheral arterial disease. Med Sci Sports Exerc, 2001, 33(12): 2016-2021.
19.	Zhu LN, Ren Y, Chen JQ, et al. Effects of myogenin on muscle fiber types and key metabolic enzymes in gene transfer mice and C2C12 myoblasts. Gene, 2013, 532(2): 246-252.
20.	Guo J, Shan T, Wu T, et al. Comparisons of different muscle metabolic enzymes and muscle fiber types in Jinhua and Landrace pigs. J Anim Sci, 2011, 89(1): 185-191.
21.	Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature, 2002, 418(6899): 797-801.
22.	Wang YX, Zhang CL, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol, 2004, 2(10): e294.
23.	Gan ZJ, Rumsey J, Hazen BC, et al. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J Clin Invest, 2013, 123(6): 2564-2575.
24.	David G, Nguyen K, Barrett EF. Early vulnerability to ischemia/reperfusion injury in motor terminals innervating fast muscles of SOD1-G93A mice. Exp Neurol, 2007, 204(1): 411-420.
25.	Bovenberg MS, Degeling MH, De Ruiter GC, et al. Type grouping in rat skeletal muscle after crush injury. J Neurosurg, 2011, 114(5): 1449-1456.

1. Emanueli C, Salis MB, Milia AF, et al. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Hypertension, 2002, 40(3): 402.
2. Karatzas A, Katsanos K, Lilis I, et al. NGF promotes hemodynamic recovery in a rabbit hindlimb ischemic model through trkA-and VEGFR2-dependent pathways. J Cardiovasc Pharmacol, 2013, 62(3): 270-277.
3. Katare R, Stroemer P, Hicks C, et al. Clinical-grade human neural stem cells promote reparative neovascularization in mouse models of hindlimb ischemia. Arterioscler Thromb Vasc Biol, 2014, 34(2): 408-418.
4. Stabile E, Burnett MS, Watkins C, et al. Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice. Circulation, 2003, 108(2): 205-210.
5. Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals, 2005, 14(5): 207-221.
6. Renault MA, Chapouly C, Yao Q, et al. Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival. Circ Res, 2013, 112(5): 762-770.
7. Jadhao CS, Bhatwadekar AD, Jiang Y, et al. Nerve growth factor promotes endothelial progenitor cell-mediated angiogenic responses. Invest Ophthalmol Vis Sci, 2012, 53(4): 2030-2037.
8. Liu X, Li Y, Liu Y, et al. Endothelial progenitor cells (EPCs) mobilized and activated by neurotrophic factors may contribute to pathologic neovascularization in diabetic retinopathy. Am J Pathol, 2010, 176(1): 504-515.
9. Steinle JJ, Granger HJ. Nerve growth factor regulates human choroidal, but not retinal, endothelial cell migration and proliferation. Auton Neurosci, 2003, 108(1/2): 57-62.
10. Romon R, Adriaenssens E, Lagadec C, et al. Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Mol Cancer, 2010, 9: 157.
11. Trapani L, Melli L, Segatto M, et al. Effects of myosin heavy chain (MHC) plasticity induced by HMGCoA-reductase inhibition on skeletal muscle functions. FASEB J, 2011, 25(11): 4037-4047.
12. Bloemink MJ, Adamek N, Reggiani C, et al. Kinetic analysis of the slow skeletal myosin MHC-1 isoform from bovine masseter muscle. J Mol Biol, 2007, 373(5): 1184-1197.
13. Schiaffino S, Reggiani C. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev, 1996, 76(2): 371-423.
14. Furrer R, De Haan A, Bravenboer N, et al. Effects of concurrent training on oxidative capacity in rat gastrocnemius muscle. Med Sci Sports Exerc, 2013, 45(9): 1674-1683.
15. Matsakas A, Yadav V, Lorca S, et al. Revascularization of ischemic skeletal muscle by estrogen-related receptor-gamma. Circ Res, 2012, 110(8): 1087-1096.
16. Chakkalakal JV, Kuang S, Buffelli M, et al. Mouse transgenic lines that selectively label typeⅠ, typeⅡA, and typesⅡX+B skeletal muscle fibers. Genesis, 2012, 50(1): 50-58.
17. Sillen MJ, Franssen FM, Gosker HR, et al. Metabolic and structural changes in lower-limb skeletal muscle following neuromuscular electrical stimulation: a systematic review. PLoS One, 2013, 8(9): e69391.
18. McGuigan MR, Bronks R, Newton RU, et al. Muscle fiber characteristics in patients with peripheral arterial disease. Med Sci Sports Exerc, 2001, 33(12): 2016-2021.
19. Zhu LN, Ren Y, Chen JQ, et al. Effects of myogenin on muscle fiber types and key metabolic enzymes in gene transfer mice and C2C12 myoblasts. Gene, 2013, 532(2): 246-252.
20. Guo J, Shan T, Wu T, et al. Comparisons of different muscle metabolic enzymes and muscle fiber types in Jinhua and Landrace pigs. J Anim Sci, 2011, 89(1): 185-191.
21. Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature, 2002, 418(6899): 797-801.
22. Wang YX, Zhang CL, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol, 2004, 2(10): e294.
23. Gan ZJ, Rumsey J, Hazen BC, et al. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J Clin Invest, 2013, 123(6): 2564-2575.
24. David G, Nguyen K, Barrett EF. Early vulnerability to ischemia/reperfusion injury in motor terminals innervating fast muscles of SOD1-G93A mice. Exp Neurol, 2007, 204(1): 411-420.
25. Bovenberg MS, Degeling MH, De Ruiter GC, et al. Type grouping in rat skeletal muscle after crush injury. J Neurosurg, 2011, 114(5): 1449-1456.

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Nerve Growth Factor Promotes Angiogenesis and Skeletal Muscle Fiber Remodeling in A Mouse Hindlimb Ischemic Model

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