Increased perfusion and angiogenesis in a hindlimb ischemia model with plasmid FGF-2 delivered by noninvasive electroporation.
Gene therapy approaches delivering fibroblast growth factor-2 (FGF-2) have shown promise as a potential treatment for increasing blood flow to ischemic limbs. Currently, effective noninvasive techniques to deliver plasmids encoding genes of therapeutic interest, such as FGF-2, are limited. We sought to determine if intradermal injection of plasmid DNA encoding FGF-2 (pFGF) followed by noninvasive cutaneous electroporation (pFGFE+) could increase blood flow and angiogenesis in a rat model of hindlimb ischemia. pFGFE+ or control treatments were administered on postoperative day 0. Compared to injection of pFGF alone (pFGFE-), delivery of pFGFE+ significantly increased FGF-2 expression for 10 days. Further, the increase in FGF-2 expression with pFGFE+ was sufficient to significantly increase ischemic limb blood flow, measured by laser Doppler perfusion imaging, beginning on postoperative day 3. Ischemic limb blood flow in the pFGFE+ treatment group remained significantly higher than all control groups through the end point of the study, postoperative day 14. Immunohistochemical staining of gastrocnemius cross sections determined there was a twofold increase in capillary density in the pFGFE+ treatment group. Our results suggest that pFGFE+ is a potential noninvasive, nonviral therapeutic approach to increase perfusion and angiogenesis for the treatment of limb ischemia.
Ferraro
B
B
Department of Molecular Medicine, University of South Florida, Tampa, FL, USA.
Cruz
Y L
YL
Baldwin
M
M
Coppola
D
D
Heller
R
R
D000818:Animals; D004195:Disease Models, Animal; D018274:Electroporation; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000628:therapy*; D018919:Neovascularization, Physiologic; D016491:Peripheral Vascular Diseases / Q000628:therapy; D051381:Rats; D012039:Regional Blood Flow
D016222:Fibroblast Growth Factor 2
Lancet. 2002 Jun 15;359(9323):2053-8
12086757
Hum Gene Ther. 1999 Apr 10;10(6):965-76
10223730
J Surg Res. 2004 Jul;120(1):37-46
15172188
J Vasc Surg. 2000 Jan;31(1 Pt 2):S1-S296
10666287
Circulation. 2001 Nov 6;104(19):2344-50
11696476
Mol Ther. 2000 Aug;2(2):140-6
10947941
Mol Ther. 2001 Feb;3(2):249-55
11237682
DNA Cell Biol. 2001 Jan;20(1):21-6
11242540
Nat Med. 2003 May;9(5):604-13
12669032
Vaccine. 2008 Jan 17;26(3):440-8
18082294
Pharm Res. 2001 Jan;18(1):61-6
11336354
Cell. 1991 Sep 20;66(6):1095-104
1717155
Atherosclerosis. 2008 Sep;200(1):51-7
18258238
Gene Ther. 2001 Dec;8(23):1808-12
11803401
Nat Med. 2002 Aug;8(8):831-40
12091877
Biochem Biophys Res Commun. 2007 Sep 7;360(4):752-8
17624309
Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1-75
17140820
Clin Exp Pharmacol Physiol. 2006 Jul;33(7):623-7
16789930
Nat Med. 2003 Jun;9(6):694-701
12778168
J Cell Physiol. 2008 Nov;217(2):319-27
18506785
Cardiovasc Res. 2008 Nov 1;80(2):263-70
18647755
Br J Pharmacol. 2003 Oct;140(4):637-46
14534147
Circ J. 2007 Aug;71(8):1181-6
17652878
Eur J Vasc Endovasc Surg. 1998 Jan;15(1):36-43
9518998
J Mol Cell Cardiol. 2002 Jul;34(7):775-87
12099717
Hum Gene Ther. 2000 Nov 1;11(16):2253-9
11084683
Cytokine Growth Factor Rev. 2005 Apr;16(2):159-78
15863032
Vaccine. 2007 Feb 26;25(10):1814-23
17240007
J Vasc Res. 2009;46(1):45-54
18552506
Eur J Clin Invest. 2001 Aug;31(8):651-66
11473566
Vasc Med. 2001 Nov;6(4):235-9
11958389
J Clin Pharmacol. 2001 Apr;41(4):378-85
11304894
J Invest Dermatol. 2004 Oct;123(4):791-8
15373787
Circ Res. 2002 May 17;90(9):966-73
12016262
Int J Pharm. 2005 Apr 27;294(1-2):53-63
15814230
JAMA. 1995 Sep 27;274(12):975-80
7674529
Vaccine. 2002 Sep 10;20(27-28):3399-3408
12213410
Circ Res. 2002 Nov 15;91(10):923-30
12433837
Vascul Pharmacol. 2006 Jun;44(6):395-405
16698324
Circulation. 1999 May 25;99(20):2682-7
10338463
J Am Coll Cardiol. 2000 Oct;36(4):1239-44
11028477
Nature. 2000 Sep 14;407(6801):249-57
11001068
Wound Repair Regen. 2006 Sep-Oct;14(5):618-24
17014675
Gene Ther. 2004 Dec;11(24):1780-5
15470477
Nat Med. 2003 Jun;9(6):653-60
12778163