Role of Angiogenesis in Endodontics: Contributions of Stem Cells and Proangiogenic and Antiangiogenic Factors to Dental Pulp Regeneration

  • Mohammad Ali Saghiri
    Address requests for reprints to Dr Mohammad Ali Saghiri, Department of Ophthalmology and Visual Sciences, 1111 Highland Avenue, 9418, Wisconsin Institute for Medical Research (WIMR), Madison, WI 53705.
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

    Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

    McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Search for articles by this author
  • Armen Asatourian
    Kamal Asgar Research Center, Shiraz, Iran
    Search for articles by this author
  • Christine M. Sorenson
    McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

    Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Search for articles by this author
  • Nader Sheibani
    Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

    Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

    McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
    Search for articles by this author
Published:January 31, 2015DOI:



      Dental pulp regeneration is a part of regenerative endodontics, which includes isolation, propagation, and re-transplantation of stem cells inside the prepared root canal space. The formation of new blood vessels through angiogenesis is mandatory to increase the survival rate of re-transplanted tissues. Angiogenesis is defined as the formation of new blood vessels from preexisting capillaries, which has great importance in pulp regeneration and homeostasis. Here the contribution of human dental pulp stem cells and proangiogenic and antiangiogenic factors to angiogenesis process and regeneration of dental pulp is reviewed.


      A search was performed on the role of angiogenesis in dental pulp regeneration from January 2005 through April 2014. The recent aspects of the relationship between angiogenesis, human dental pulp stem cells, and proangiogenic and antiangiogenic factors in regeneration of dental pulp were assessed.


      Many studies have indicated an intimate relationship between angiogenesis and dental pulp regeneration. The contribution of stem cells and mechanical and chemical factors to dental pulp regeneration has been previously discussed.


      Angiogenesis is an indispensable process during dental pulp regeneration. The survival of inflamed vital pulp and engineered transplanted pulp tissue are closely linked to the process of angiogenesis at sites of application. However, the detailed regulatory mechanisms involved in initiation and progression of angiogenesis in pulp tissue require investigation.

      Key Words

      To read this article in full you will need to make a payment


      Subscribe to Journal of Endodontics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Risau W.,
        • Flamme I.
        Ann Rev Cell Dev Biol. 1995; 11: 73-91
        • Flamme I.
        • Frölich T.
        • Risau W.
        Molecular mechanisms of vasculogenesis and embryonic angiogenesis.
        J Cell Physiol. 1997; 173: 206-210
        • Behzadian M.A.
        • Bartoli A.B.
        • El-Remessy B.
        • et al.
        Cellular and molecular mechanisms of retinal angiogenesis.
        in: Penn J.S. Retinal and Choroidal Angiogenesis. Springer, New York2008: 119
        • Carmeliet P.
        • Jain R.K.
        Molecular mechanisms and clinical applications of angiogenesis.
        Nature. 2011; 473: 298-307
        • Bhadada S.V.
        • Goyal B.R.
        • Patel M.M.
        Angiogenic targets for potential disorders.
        Fundam Clin Pharmacol. 2011; 25: 29-47
        • Carmeliet P.
        • Jain R.K.
        Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases.
        Nat Rev Drug Discov. 2011; 10: 417-427
        • Folkman J.
        Is angiogenesis an organizing principle in biology and medicine?.
        J Pediatr Surg. 2007; 42: 1-11
        • Burri P.H.
        • Hlushchuk R.
        • Djonov V.
        Intussusceptive angiogenesis: its emergence, its characteristics, and its significance.
        Dev Dyn. 2004; 231: 474-488
        • Prior B.M.
        • Yang H.T.
        • Terjung R.L.
        What makes vessels grow with exercise training?.
        J Appl Physiol. 2004; 97: 1119-1128
        • Sheppard D.
        Endothelial integrins and angiogenesis: not so simple anymore.
        J Clin Invest. 2002; 110: 913-914
        • Stegmann T.J.
        • Hoppert T.
        • Schneider A.
        • et al.
        Induction of myocardial neoangiogenesis by human growth factors: a new therapeutic approach in coronary heart disease.
        Herz. 2000; 25 (in German): 589-599
        • Stegmann T.J.
        FGF-1: a human growth factor in the induction of neoangiogenesis.
        Expert Opin Investig Drugs. 1998; 7: 2011-2015
        • Folkman J.
        Angiogenic therapy of the human heart.
        Circulation. 1998; 97: 628-629
        • Wagoner L.E.
        • Merrill W.
        • Jacobs J.
        • et al.
        Angiogenesis protein therapy with human fibroblast growth factor (FGF-1) results of a phase I open label, dose escalation study in subjects with CAD not eligible for PCI or CABG.
        Circulation. 2007; 116: 443
        • Gronthos S.
        • Mankani M.
        • Brahim J.
        • et al.
        Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo.
        Proc Natl Acad Sci U S A. 2000; 97: 13625-13630
        • About I.
        • Bottero M.J.
        • de Denato P.
        • et al.
        Human dentin production in vitro.
        Exp Cell Res. 2000; 258: 33-41
        • Nakashima M.
        • Akamine A.
        The application of tissue engineering to regeneration of pulp and dentin in endodontics.
        J Endod. 2005; 31: 711-718
        • Murray P.E.
        • Garcia-Godoy F.
        • Hargreaves K.
        Regenerative endodontics: a review of current status and a call for action.
        J Endod. 2007; 33: 377-390
        • Langer R.
        • Vacanti J.P.
        Tissue engineering.
        Science. 1993; 260: 920-926
        • Rahaman M.N.
        • Mao J.J.
        Stem cell-based composite tissue constructs for regenerative medicine.
        Biotechnol Bioeng. 2005; 91: 261-284
        • Laschke M.W.
        • Harder Y.
        • Amon M.
        • et al.
        Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes.
        Tissue Eng. 2006; 12: 2093-2104
        • Tran-Hung L.
        • Mathieu S.
        • About I.
        Role of human pulp fibroblasts in angiogenesis.
        J Dent Res. 2006; 85: 819-823
        • Saghiri M.A.
        • Asatourian A.
        • Sheibani N.
        Angiogenesis in regenerative dentistry.
        Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 119: 122
        • Papaccio G.
        • Graziano A.
        • d'Aquino R.
        • et al.
        Long-term cryopreservation of dental pulp stem cells (SBP-DPSCs) and their differentiated osteoblasts: a cell source for tissue repair.
        J Cell Physiol. 2006; 208: 319-325
        • Zhang W.
        • Walboomers X.F.
        • Shi S.
        • et al.
        Multilineage differentiation potential of stem cells derived from human dental pulp after cryopreservation.
        Tissue Eng. 2006; 12: 2813-2823
        • Krebsbach P.H.
        • Robey P.G.
        Dental and skeletal stem cells: potential cellular therapeutics for craniofacial regeneration.
        J Dent Educ. 2002; 66: 766-773
        • Gronthos S.
        • Brahim J.
        • Li W.
        • et al.
        Stem cell properties of human dental pulp stem cells.
        J Dent Res. 2002; 81: 531-535
        • Nakashima M.
        • Iohara K.
        • Ishikawa M.
        • et al.
        Stimulation of reparative dentin formation by ex vivo gene therapy using dental pulp stem cells electrotransfected with growth/differentiation factor 11 (Gdf11).
        Hum Gene Ther. 2004; 15: 1045-1053
        • Sieveking D.P.
        • Ng M.K.
        Cell therapies for therapeutic angiogenesis: back to the bench.
        Vasc Med. 2009; 14: 153-166
        • Bronckaers A.
        • Hilkens P.
        • Fanton Y.
        • et al.
        Angiogenic properties of human dental pulp stem cells.
        PLoS One. 2013; 8: e71104
        • Hilkens P.
        • Fanton Y.
        • Martens W.
        • et al.
        Pro-angiogenic impact of dental stem cells in vitro and vivo.
        Stem Cell Res. 2014; 12: 778-790
        • Tran-Hung L.
        • Laurent P.
        • Camps J.
        • About I.
        Quantification of angiogenic growth factors released by human dental cells after injury.
        Arch Oral Biol. 2008; 53: 9-13
        • Aranha A.M.
        • Zhang Z.
        • Neiva K.G.
        • et al.
        Hypoxia enhances the angiogenic potential of human dental pulp cells.
        J Endod. 2010; 36: 1633-1637
        • Matsushita K.
        • Motani R.
        • Sakuta T.
        • et al.
        The role of vascular endothelial growth factor in human dental pulp cells: induction of chemotaxis, proliferation, and differentiation and activation of the AP-1-dependent signaling pathway.
        J Dent Res. 2000; 79: 1596-1603
        • Nakashima M.
        • Iohara K.
        • Sugiyama M.
        Human dental pulp stem cells with highly angiogenic and neurogenic potential for possible use in pulp regeneration.
        Cytokine Growth Factor Rev. 2009; 20: 435-440
        • d'Aquino R.
        • Graziano A.
        • Sampaolesi M.
        • et al.
        Human postnatal dental pulp cells co-differentiate into osteoblasts and endotheliocytes: a pivotal synergy leading to adult bone tissue formation.
        Cell Death Differ. 2007; 14: 1162-1171
        • Karbanova J.
        • Soukup T.
        • Suchanek J.
        • et al.
        Characterization of dental pulp stem cells from impacted third molars cultured in low serum-containing medium.
        Cells Tissues Organs. 2011; 193: 344-365
        • Marchionni C.
        • Bonsi L.
        • Alviano F.
        • et al.
        Angiogenic potential of human dental pulp stromal (stem) cells.
        Int J Immunopathol Pharmacol. 2009; 22: 699-706
        • Janebodin K.
        • Zeng Y.
        • Buranaphatthana W.
        • et al.
        VEGFR2-dependent angiogenic capacity of pericyte-like dental pulp stem cells.
        J Dent Res. 2013; 92: 524-531
        • Cordeiro M.M.
        • Dong Z.
        • Kaneko T.
        • et al.
        Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth.
        J Endod. 2008; 34: 962-969
        • Bento L.W.
        • Zhang Z.
        • Imai A.
        • et al.
        Endothelial differentiation of SHED requires MEK1/ERK signaling.
        J Dent Res. 2013; 92: 51-57
        • Liu W.
        • Gong Q.
        • Ling J.
        • et al.
        Role of miR-424 on angiogenic potential in human dental pulp cells.
        J Endod. 2014; 40: 76-82
        • Kim J.J.
        • Kim S.J.
        • Kim Y.S.
        • et al.
        The role of SIRT1 on angiogenic and odontogenic potential in human dental pulp cells.
        J Endod. 2012; 38: 899-906
        • Dissanayaka W.L.
        • Zhan X.
        • Zhang C.
        • et al.
        Coculture of dental pulp stem cells with endothelial cells enhances osteo-/odontogenic and angiogenic potential in vitro.
        J Endod. 2012; 38: 454-463
        • Nakashima M.
        • Iohara K.
        Regeneration of dental pulp by stem cells.
        Adv Dent Res. 2012; 23: 313-319
        • Milkiewicz M.
        • Brown M.D.
        • Egginton S.
        • Hudlicka O.
        Association between shear stress, angiogenesis, and VEGF in skeletal muscles in vivo.
        Microcirculation. 2001; 8: 229-241
        • Derringer K.A.
        • Jaggers D.C.
        • Linden R.W.
        Angiogenesis in human dental pulp following orthodontic tooth movement.
        J Dent Res. 1996; 75: 1761-1766
        • Derringer K.A.
        • Linden R.W.
        Enhanced angiogenesis induced by diffusible angiogenic growth factors released from human dental pulp explants of orthodontically moved teeth.
        Eur J Orthod. 1998; 20: 357-367
        • Derringer K.A.
        • Linden R.W.
        Angiogenic growth factors released in human dental pulp following orthodontic force.
        Arch Oral Biol. 2003; 48: 285-291
        • Derringer K.A.
        • Linden R.W.
        Vascular endothelial growth factor, fibroblast growth factor 2, platelet derived growth factor and transforming growth factor beta released in human dental pulp following orthodontic force.
        Arch Oral Biol. 2004; 49: 631-641
        • Grünheid T.
        • Morbach B.A.
        • Zentner A.
        Pulpal cellular reactions to experimental tooth movement in rats.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104: 434-441
        • Derringer K.
        • Linden R.
        Epidermal growth factor released in human dental pulp following orthodontic force.
        Eur J Orthod. 2007; 29: 67-71
        • Nakashima M.
        • Reddi A.H.
        The application of BMPs to dental tissue engineering.
        Nat Biotech. 2003; 21: 1025-1032
        • Roberts-Clark D.J.
        • Smith A.J.
        Angiogenic growth factors in human dentine matrix.
        Arch Oral Biol. 2000; 45: 1013-1016
        • Bagri A.
        • Kouros-Mehr H.
        • Leong K.G.
        • Plowman G.D.
        Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale.
        Trends Mol Med. 2010; 16: 122-132
        • Wang R.
        • Chadalavada K.
        • Wishire J.
        • et al.
        Glioblastoma stem-like cells give rise to tumour endothelium.
        Nature. 2010; 468: 829-833
        • Ricci-Vitiani L.
        • Pallini R.
        • Biffoni M.
        • et al.
        Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.
        Nature. 2010; 468: 824-828
        • Gerwins P.
        • Sköldenberg E.
        • Claesson-Welsh L.
        Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis.
        Crit Rev Oncol Hematol. 2000; 34: 185-194
        • Holderfield M.T.
        • Hughes C.C.W.
        Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-b in vascular morphogenesis.
        Circ Res. 2008; 102: 637-652
        • Ferrara N.
        Vascular endothelial growth factor.
        Eur J Cancer. 1996; 32A: 2413-2422
        • Grando Mattuella L.
        • Westphalen Bento L.
        • de Figueiredo J.A.
        • et al.
        Vascular endothelial growth factor and its relationship with the dental pulp.
        J Endod. 2011; 37: 26-30
        • Mullane E.M.
        • Dong Z.
        • Sedgley C.M.
        • et al.
        Effects of VEGF and FGF2 on the revascularization of severed human dental pulps.
        J Dent Res. 2008; 87: 1144-1148
        • Virtej A.
        • Løes S.
        • Iden O.
        • et al.
        Vascular endothelial growth factors signaling in normal human dental pulp: a study of gene and protein expression.
        Eur J Oral Sci. 2013; 12: 92-100
        • Güven G.
        • Altun C.
        • Günhan O.
        • et al.
        Co-expression of cyclooxygenase-2 and vascular endothelial growth factor in inflamed human pulp: an immunohistochemical study.
        J Endod. 2007; 33: 18-20
        • Scheven B.A.
        • Man J.
        • Millard J.L.
        • et al.
        VEGF and odontoblast like cells: stimulation by low frequency ultrasound.
        Arch Oral Biol. 2009; 54: 185-191
        • Ornitz D.M.
        • Itoh N.
        Fibroblast growth factors.
        Genome Biology. 2001; 2 (reviews3005.1–3005.12.)
        • Blaber M.
        • DiSalvo J.
        • Thomas K.A.
        X-ray crystal structure of human acidic fibroblast growth factor.
        Biochemistry. 1996; 35: 2086-2094
        • Khurana R.
        • Simons M.
        Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease.
        Trends Cardiovasc Med. 2003; 13: 116-122
        • Takeuchi N.
        • Hayashi Y.
        • Murakami M.
        • et al.
        Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony.
        Oral Dis. 2015; 21: 113-122
        • Li Z.
        • Sae-Lim V.
        Comparison of acidic fibroblast growth factor on collagen carrier with calcium hydroxide as pulp capping agents in monkeys.
        Dent Traumatol. 2007; 23: 278-286
        • Hannink M.
        • Donoghue D.J.
        Structure and function of platelet-derived growth factor (PDGF) and related proteins.
        Biochim Biophys Acta. 1989; 989: 1-10
        • Keck P.J.
        • Hauser S.D.
        • Krivi G.
        • et al.
        Vascular permeability factor, an endothelial cell mitogen related to PDGF.
        Science. 1989; 246: 1309-1312
        • Matsuoka J.
        • Grotendorst G.R.
        Two peptides related to platelet-derived growth factor are present in human wound fluid.
        Proc Natl Acad Sci U S A. 1989; 86: 4416-4420
        • Thurston G.
        Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis.
        Cell Tissue Res. 2003; 314: 61-68
        • El Karim I.A.
        • Linden G.J.
        • Irwin C.R.
        • Lundy F.T.
        Neuropeptides regulate expression of angiogenic growth factors in human dental pulp fibroblasts.
        J Endod. 2009; 35: 829-833
        • Haas T.L.
        • Milkiewicz M.
        • Davis S.J.
        • et al.
        Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle.
        Am J Physiol Heart Circ Physiol. 2000; 279: H1540-H1547
        • Zheng L.
        • Amano K.
        • Iohara K.
        • et al.
        Matrix metalloproteinase-3 accelerates wound healing following dental pulp injury.
        Am J Pathol. 2009; 175: 1905-1914
        • Muromachi K.
        • Kamio N.
        • Narita T.
        • et al.
        MMP-3 provokes CTGF/CCN2 production independently of protease activity and dependently on dynamin-related endocytosis, which contributes to human dental pulp cell migration.
        J Cell Biochem. 2012; 113: 1348-1358
        • Ozeki N.
        • Yamaguchi H.
        • Kawai R.
        • et al.
        Cytokines induce MMP-3-regulated proliferation of embryonic stem cell-derived odontoblast-like cells.
        Oral Dis. 2014; 20: 505-513
        • Broudy V.C.
        Stem cell factor and hematopoiesis.
        Blood. 1997; 90: 1345-1364
        • Lapidot T.
        • Dar A.
        • Kollet O.
        How do stem cells find their way home?.
        Blood. 2005; 106: 1901-1910
        • Pan S.
        • Dangaria S.
        • Gopinathan G.
        • et al.
        SCF promotes dental pulp progenitor migration, neovascularization, and collagen remodeling: potential applications as a homing factor in dental pulp regeneration.
        Stem Cell Rev. 2013; 9: 655-667
        • Mundy G.
        • Garrett R.
        • Harris S.
        • et al.
        Stimulation of bone formation in vitro and in rodents by statins.
        Science. 1999; 286: 1946-1949
        • Limjeerajarus C.N.
        • Osathanon T.
        • Manokawinchoke J.
        • Pavasant P.
        Iloprost up-regulates vascular endothelial growth factor expression in human dental pulp cells in vitro and enhances pulpal blood flow in vivo.
        J Endod. 2014; 40: 925-930
        • Hamelin B.A.
        • Turgeon J.
        Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors.
        Trends Pharmacol Sci. 1998; 19: 26-37
        • Min K.S.
        • Lee Y.M.
        • Hong S.O.
        • Kim E.C.
        Simvastatin promotes odontoblastic differentiation and expression of angiogenic factors via heme oxygenase-1 in primary cultured human dental pulp cells.
        J Endod. 2010; 36: 447-452
        • Kim M.K.
        • Park H.J.
        • Kim Y.D.
        • et al.
        Hinokitiol increases the angiogenic potential of dental pulp cells through ERK and p38MAPK activation and hypoxia-inducible factor-1α (HIF-1α) upregulation.
        Arch Oral Biol. 2014; 59: 102-110
        • Trimmel K.
        • Cvikl B.
        • Müller H.D.
        • et al.
        L-mimosine increases the production of vascular endothelial growth factor in human tooth slice organ culture model.
        Int Endod J. 2014;
        • Kajiya M.
        • Shiba H.
        • Komatsuzawa H.
        • et al.
        The antimicrobial peptide LL37 induces the migration of human pulp cells: a possible adjunct for regenerative endodontics.
        J Endod. 2010; 36: 1009-1013
        • Izumi T.
        • Eida T.
        • Matsumoto N.
        • Inoue H.
        Immunohistochemical localization of metallothionein in dental pulp after cavity preparation of rat molars.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104: e133-e137
        • Geerlings S.E.
        • Hoepelman A.I.
        Immune dysfunction in patients with diabetes mellitus.
        FEMS Immunol Med Microbiol. 1999; 26: 259-265
        • Delamaire M.
        • Maugendre D.
        • Moreno M.
        • et al.
        Impaired leukocyte functions in diabetic patients.
        Diabetes Med. 1997; 14: 29-34
        • Joshi N.
        • Caputo G.M.
        • Weitekamp M.R.
        • Karchmer A.W.
        Infections in patients with diabetes mellitus.
        N Engl J Med. 1999; 341: 1906-1912
        • Grossi S.G.
        • Genco R.J.
        Periodontal disease and diabetes mellitus: a two-way relationship.
        Ann Periodontol. 1998; 3: 51-61
        • Garber S.E.
        • Shabahang S.
        • Escher A.P.
        • Torabinejad M.
        The effect of hyperglycemia on pulpal healing in rats.
        J Endod. 2009; 35: 60-62
        • Maurer A.M.
        • Zhou B.
        • Han Z.C.
        Roles of platelet factor 4 in hematopoiesis and angiogenesis.
        Growth Factor. 2006; 24: 242-252