title: Flow increase is decisive to initiate angiogenesis in veins exposed to altered hemodynamics.
abstract: Exposing a vein to altered hemodynamics by creating an arteriovenous (AV) shunt evokes considerable vessel formation that may be of therapeutic potential. However, it is unclear whether the introduction of oscillatory flow and/or flow increase is decisive. To distinguish between these mechanical stimuli we grafted a femoral vein into the arterial flow pathway of the contralateral limb in rats creating an arterioarterial (AA) loop (n = 7). Alternatively, we connected the femoral artery and vein using the vein graft, whereby we created an AV-loop (n = 27). Vessel loops were embedded in a fibrin filled chamber and blood flow was measured by means of flow probes immediately after surgery (day 0) and 15 days after loop creation. On day 15, animals were sacrificed and angiogenesis was evaluated using μCT and histological analysis. Mean flow increased from 0.5 to 2.4 mL/min and was elevated throughout the cardiac cycle at day 0 in AV-loops whereas, as expected, it remained unchanged in AA-loops. Flow in AV-loops decreased with time, and was at day 15 not different from untreated femoral vessels or AA-loop grafts. Pulsatile flow oscillations were similar in AV-and AA-loops at day 0. The flow amplitude amounted to ~1.3 mL/min which was comparable to values in untreated arteries. Flow amplitude remained constant in AA-loops, whereas it decreased in AV-loops (day 15: 0.4 mL/min). A large number of newly formed vessels were present in AV-loops at day 15 arising from the grafted vein. In marked contrast, angiogenesis originating from the grafted vein was absent in AA-loops. We conclude that exposure to substantially increased flow is required to initiate angiogenesis in grafted veins, whereas selective enhancement of pulsatile flow is unable to do so. This suggests that indeed flow and most likely wall shear stress is decisive to initiate formation of vessels in this hemodynamically driven angiogenesis model.
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg, Heidelberg, Germany.
authors: Volker J
authors: VJ
authors: Schmidt
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Johannes G
authors: JG
authors: Hilgert
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Jennifer M
authors: JM
authors: Covi
authors: Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg, Heidelberg, Germany.
authors: Nico
authors: N
authors: Leibig
authors: Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg, Heidelberg, Germany.
authors: Johanna O
authors: JO
authors: Wietbrock
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Andreas
authors: A
authors: Arkudas
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Elias
authors: E
authors: Polykandriotis
authors: Department for Physiology, Universität zu Lübeck, Lübeck, Germany.
authors: Cor
authors: C
authors: de Wit
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Raymund E
authors: RE
authors: Horch
authors: Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Department for Hand-, Plastic- and Reconstructive Surgery, BG Unfallklinik Ludwigshafen, Universität Heidelberg, Heidelberg, Germany.
authors: Ulrich
authors: U
authors: Kneser
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003971:Diastole; D005268:Femoral Vein / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology*; D008297:Male; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011917:Rats, Inbred Lew; D012039:Regional Blood Flow / Q000502:physiology*
chemical_list: D018031:Connexin 43; D012333:RNA, Messenger
references: Br J Plast Surg. 2000 Jan;53(1):51-7
references: 10657450
references: Tissue Eng. 2000 Dec;6(6):595-603
references: 11103081
references: J Vasc Surg. 2001 Mar;33(3):561-9
references: 11241128
references: Nat Med. 2003 Jun;9(6):653-60
references: 12778163
references: Circ Res. 2003 Nov 14;93(10):e136-42
references: 14563712
references: Cell Tissue Res. 2003 Oct;314(1):107-17
references: 14574551
references: Plast Reconstr Surg. 2003 Nov;112(6):1636-44
references: 14578795
references: Development. 2004 Jan;131(2):361-75
references: 14681188
references: Am J Physiol. 1992 Mar;262(3 Pt 2):H846-51
references: 1532695
references: Med Biol Eng Comput. 2005 Jan;43(1):126-30
references: 15742730
references: Br J Plast Surg. 2005 Dec;58(8):1104-14
references: 16043148
references: Biol Chem. 2006 Jan;387(1):3-9
references: 16497158
references: FASEB J. 2007 Feb;21(2):511-22
references: 17172640
references: Curr Pharm Biotechnol. 2007 Feb;8(1):11-25
references: 17311549
references: Microvasc Res. 2008 Jan;75(1):25-33
references: 17544455
references: Mol Med. 2007 Sep-Oct;13(9-10):480-7
references: 17762899
references: Microsurgery. 2007;27(7):623-9
references: 17868145
references: Pharmacol Rep. 2008 Jan-Feb;60(1):68-74
references: 18276987
references: Cardiovasc Res. 2008 Aug 1;79(3):509-18
references: 18445604
references: Development. 2008 Aug;135(15):2659-68
references: 18599509
references: Nature. 2010 Apr 22;464(7292):1196-200
references: 20364122
references: Development. 2010 Jul;137(13):2187-96
references: 20530546
references: Tissue Eng Part C Methods. 2010 Dec;16(6):1503-14
references: 20575690
references: J Vasc Surg. 2011 Feb;53(2):435-44
references: 21030196
references: Nature. 2011 May 19;473(7347):298-307
references: 21593862
references: Int J Dev Biol. 2011;55(4-5):419-29
references: 21858767
references: J Cell Physiol. 2012 Jun;227(6):2710-21
references: 21898411
references: Plast Reconstr Surg. 2012 Jan;129(1):55e-65e
references: 22186585
references: F1000 Biol Rep. 2012;4:1
references: 22238515
references: J Biomed Mater Res A. 2012 Sep;100(9):2302-11
references: 22508579
references: Am J Physiol Cell Physiol. 2012 Sep 15;303(6):C595-606
references: 22744008
references: PLoS One. 2012;7(7):e42287
references: 22848755
references: Tissue Eng Part C Methods. 2013 Jun;19(6):479-86
references: 23189952
references: Cardiovasc Res. 2013 Nov 1;100(2):252-61
references: 23812297
references: J Cell Mol Med. 2013 Oct;17(10):1197-206
references: 24118692
references: PLoS One. 2013 Nov 13;8(11):e78782
references: 24236049
references: Microcirculation. 2014 May;21(4):290-300
references: 24471792
references: J Cell Mol Med. 2014 Jul;18(7):1478-85
references: 24801710
references: Surg Forum. 1979;30:530-1
references: 395707
references: Plast Reconstr Surg. 1980 Jul;66(1):109-15
references: 6156468
references: Nature. 1997 Apr 17;386(6626):671-4
references: 9109485
references: Circ Res. 1998 Apr 20;82(7):786-93
references: 9562438
references: Circ Res. 1998 Sep 21;83(6):636-43
references: 9742059