Rapid re-endothelialization following balloon angioplasty can reduce restenosis by inhibiting smooth muscle cell migration and proliferation. However, formation of a neointima layer following angioplasty can be inhibited due to endothelial cell dysfunction and denudation. In a companion paper, it has been illustrated that mechanical loading causes a decrease in DNA synthesis in bovine aortic endothelial cells (BAECs) thus rendering them dysfunctional. The purpose of this study was to overcome BAEC dysfunction by incubation with pharmacological agents to increase DNA synthesis. Previous studies demonstrated that the adenosine dinucleotides Ap4A and Ap2A induced nitric oxide (NO) production from BAEC while Ap3A, Ap5A and Ap6A did not. This paper demonstrates that Ap4 and Ap2 A induce a 1.46- and 1.16-fold increase in DNA synthesis in mechanically stressed BAECs respectively, while Ap3A, Ap5A and Ap6A do not. Additionally, NOC-18, a slow NO release NO donor, significantly increases DNA synthesis in mechanically stressed BAECs without affecting unloaded cells. These results are consistent with NO inducing DNA synthesis in mechanically stressed BAECs.
WoodellJ. E.LaBergeM.LanganE. M.IIIHildermanR. H.In vitro strain induced endothelial cell dysfunction determined by DNA synthesisProc. Instn Mech. Engrs, Part H: J. Engineering in Medicine, 2003, 217 (H1), 13–20.
2.
EllisS. G.SavageM.FischmanD.BaimD. S.LeonM.GoldbergS.HirshfeldJ. W.ClemanM. W.TeirsteinP. S.WalkerC.BaileyS.BuchbinderM.TopolE. J.SchatzR. A.Restenosis after placement of Palmaz-Schatz stents in native coronary arteries. Initial results of a multicenter experienceCirculation, 1992, 86, 1836–1844.
3.
DobrinP. B.GrayJ. L.SchwarezT. H.In vivo models used to study intimal hyperplasia: an introduction. In Intimal Hyperplasia (Ed. DobrinP. B.), 1994, pp. 75–83 (R. G. Landes Company, Austin, TX).
4.
EllenbyM. I.ErnstC. B.CarreteroO. A.ScicliA. G.Role of nitric oxide in the effect of blood flow on neointima formationJ. Vascular Surg., 1996, 23, 314–322.
5.
BrittenM. B.ZeiherA. M.SchachingerV.Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic optionsJ. Internal Medicine, 1999, 245, 315–327.
6.
ZicheM.MorbidelliL.MasiniE.GrangerH.GeppettiP.LeddaF.Nitric oxide promotes DNA synthesis and cyclic GMP formation in endothelial cells from postcapillary venulesBiochem. Biophys. Res. Commun., 1993, 192, 1198–1203.
7.
FlodgaardH.KlenowH.Abundant amounts of diadenosine 5′, 5′-P1, P4-tetraphosphate are present and releasable, but metabolically inactive, in human plateletsBiochem. J., 1982, 208, 737–741.
8.
SchluterH.OffersE.BruggemannG.GietM. V. D.TepelM.NordhoffE.KarasM.SpiekerC.WitzelH.ZidekW.Diadenosine phosphates and the physiological control of blood pressureNature, 1994, 367, 186–188.
9.
JankowskiJ.PotthoffW.GietM. V. D.TepelM.ZidekW.SchluterH.High-performance liquid chromatography assay of the diadenosine polyphosphates in human plateletsAnalyt. Biochemistry, 1999, 269, 72–78.
WoodellJ. E.HildermanR. H.LanganE.LaBergeM.Response of human aortic endothelial cells to extracellular matrix coated membranes. In Proceedings from the Sixth World Biomaterials Congress, Hawaii, 2000, Vol. 1, p. 97.
GoochK. J.DanglerC. A.FrangosJ. A.Exogenous, basal, and flow induced nitric oxide production and endothelial cell proliferationJ. Cellular Physiol., 1997, 171, 252–258.
15.
SarkarR.WebbC.StanleyJ. C.Nitric oxide inhibition of endothelial cell mitogenesis and proliferationSurgery, 1995, 118 (2), 274–279.
16.
GrummtF.Diadenosine 5′, 5′-P1, P4-tetraphosphate triggers initiation of in vitro DNA replication in baby hamster kidney cellsProc. Natn. Acad. Sci. USA, 1978, 75, 371–375.
17.
HeidenreichS.TepelM.SchluterH.HarrachB.ZidekW.Regulation of rat mesangial cell growth by diadenosine phosphatesJ. Clin. Invest., 1995, 95, 2862–2867.
RapaportE.ZamecnikP. C.Presence of diadenosine 5′, 5′-P1, P4-tetraphosphate(Ap4A) in mammalian cells in levels varying widely with proliferative activity of the tissue: a possible positive ‘pleiotypic activator’Proc. Natn. Acad. Sci. USA, 1976, 73, 3984–3988.
20.
VarenneO.PislaruS.GillinjnsH.PeltN. V.GerardR. D.ZoldhelyiP.WerfF. V.d.CollenD.JanssensS. P.Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigsCirculation, 1998, 98, 919–926.
21.
GorogP.KovacsI. B.Inhibition of vascular smooth muscle cell migration by intact endothelium is nitric oxide mediated: Interference by oxidized low density lipoproteinsJ. Vascular Res., 35, 165–169.
22.
MatsumotoT.KomoriK.MorishitaY.SueishiK.KanedaY.SugimachiK.Hemagglutinating virus of Japan-liposome-mediated gene transfer of endothelial cell nitric oxide synthase inhibits intimal hyperplasia of canine vein grafts under flow conditions of poor runoffJ. Vascular Surgery, 1998, 27, 135–144.
23.
ZicheM.MorbidelliL.Nitric oxide and angiogenesisJ. Neurooncol., 2000, 50, 139–148.
24.
SarkarR.MeinbergE. G.StanleyJ. C.GordonD.WebbR. C.Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cellsCirculation Res., 1996, 78, 225–230.
