Advertisement

Current Hypertension Reports

, Volume 13, Issue 6, pp 409–420 | Cite as

Effects of Relaxin on Arterial Dilation, Remodeling, and Mechanical Properties

  • Kirk P. Conrad
  • Sanjeev G. Shroff
Mediators, Mechanisms, and Pathways in Tissue Injury (Heinrich Taegtmeyer and Steven Atlas, Section Editors)

Abstract

Administering relaxin to conscious rats and humans elicits systemic and renal vasodilation. The molecular mechanisms vary according to the duration of relaxin exposure—so-called “rapid” (within minutes) or “sustained” (hours to days) vasodilatory responses—both being endothelium-dependent. Rapid responses are mediated by Gαi/o protein coupling to phosphoinositol-3 kinase/Akt (protein kinase B)–dependent phosphorylation and activation of nitric oxide synthase. Sustained responses are mediated by vascular endothelial and placental growth factors, as well as increases in arterial gelatinase activity. Thus, after hours or days of relaxin treatment, respectively, arterial MMP-9 or MMP-2 hydrolyze “big” endothelin (ET) at a gly-leu bond to form ET1-32, which in turn activates the endothelial ETB receptor/nitric oxide vasodilatory pathway. Administration of relaxin to conscious rats also increases global systemic arterial compliance and passive compliance of select isolated blood vessels such as small renal arteries (SRA). The increase in SRA passive compliance is mediated by both geometric remodeling (outward) and compositional remodeling (decreased collagen). Relaxin-induced geometric remodeling has also been observed in brain parenchymal arteries, and this remodeling appears to be via the activation of peroxisome proliferator–activated receptor-γ. Given the vasodilatory and arterial remodeling properties of relaxin, the hormone may have therapeutic potential in the settings of abnormal pregnancies, heart failure, and pathologies associated with stiffening of arteries.

Keywords

Relaxin Hypertension Pregnancy Preeclampsia Heart failure Systemic hemodynamics Arterial compliance Renal circulation Artery Angiogenic growth factors Matrix metalloproteinase Endothelin Nitric oxide Osmoregulation Collagen Elastin Endothelium Smooth muscle Arterial remodeling 

Notes

Acknowledgments

The work in the authors’ laboratory would not have been possible without the invaluable contributions of many outstanding colleagues and trainees over the years, particularly Lee A. Danielson, PhD; Laura J. Parry, PhD; Jacqueline Novak, PhD; Arun Jeyabalan, MD; John M. Davison, MD; Jonathan T. McGuane, PhD (Postdoctoral Fellow); and Dan O. Debrah (Predoctoral Fellow). We gratefully acknowledge the financial support of the National Institutes of Health (K11 HD00662, RO1 HD030325, RO1 DK063321, RO1 HL067937, and R21 HL093334), the 8th Mallinckrodt Scholar Award, New Mexico Heart Association Flinn Newly Independent Investigator Award, a Grant-in-Aid from the American Heart Association (No. 0855090E), and the McGinnis Endowed Chair Funds.

Disclosure

Conflicts of Interest: K. Conrad: Honoraria for consulting on relaxin with the pharmaceutical industry and patents related to relaxin; S. Shroff: patents related to relaxin.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004;25:205–34.PubMedCrossRefGoogle Scholar
  2. 2.
    Bathgate RA, Samuel CS, Burazin TC, et al. Relaxin: new peptides, receptors and novel actions. Trends Endocrinol Metabol. 2003;14:207–13.CrossRefGoogle Scholar
  3. 3.
    Sherwood OD. Relaxin. In: Knobil E, Neill JD, Greenwald GS, Markert CL, Pfaff DW, editors. The physiology of reproduction. 2nd ed. New York: Raven; 1994. p. 861–1008.Google Scholar
  4. 4.
    Conrad KP. Emerging role of relaxin in the maternal adapations to normal pregnancy: implications for preeclampsia. Semin Nephrol. 2011;31:15–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Hisaw FL, Hisaw Jr FL, Dawson AB. Effects of relaxin on the endothelium of endometrial blood vessels in monkeys (Macaca mulatta). Endocrinol. 1967;81:375–85.CrossRefGoogle Scholar
  6. 6.
    Dallenbach-Hellweg G, Dawson AB, Hisaw FL. The effect of relaxin on the endometrium of monkeys. Histological and histochemical studies. Am J Anat. 1966;119:61–78.CrossRefGoogle Scholar
  7. 7.
    St-Louis J, Massicotte G. Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats. Life Sci. 1985;37:1351–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Bani-Sacchi T, Bigazzi M, Bani D, et al. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol. 1995;116:1589–94.PubMedGoogle Scholar
  9. 9.
    Conrad KP, Debrah DO, Novak J, et al. Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats. Endocrinol. 2004;145:3289–96.CrossRefGoogle Scholar
  10. 10.
    Debrah DO, Conrad KP, Danielson LA, Shroff SG. Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol. 2005;98:1013–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Debrah DO, Novak J, Matthews JE, et al. Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinol. 2006;147:5126–31.CrossRefGoogle Scholar
  12. 12.
    Debrah DO, Conrad KP, Jeyabalan A, et al. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension. 2005;46:745–50.PubMedCrossRefGoogle Scholar
  13. 13.
    August P, Lindheimer MD. Chronic hypertension and pregnancy. In: Lindheimer MD, Roberts JM, Cunningham GF, editors. Chesley’s hypertensive disorders in pregnancy. 3rd ed. San Diego: Academic; 2009. p. 353–68.CrossRefGoogle Scholar
  14. 14.
    Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest. 1999;103:525–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Conrad KP. Renal hemodynamics during pregnancy in chronically catheterized, conscious rats. Kidney Int. 1984;26:24–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Danielson LA, Kercher LJ, Conrad KP. Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol. 2000;279:R1298–304.Google Scholar
  17. 17.
    Novak J, Ramirez RJ, Gandley RE, et al. Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am J Physiol. 2002;283:R349–55.Google Scholar
  18. 18.
    Gandley RE, Conrad KP, McLaughlin MK. Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats. Am J Physiol. 2001;280:R1–7.Google Scholar
  19. 19.
    van Drongelen J, Pertijs J, Wouterse A et al. Contribution of different local vascular responses to mid-gestational vasodilation. Am J Obstet Gynecol 2011. Eub ahead of print.Google Scholar
  20. 20.
    van Drongelen J, Ploemen IH, Pertijs J, et al. Aging attenuates the vasodilator response to relaxin. Am J Physiol Heart Circ Physiol. 2011;300:H1609–1615.PubMedCrossRefGoogle Scholar
  21. 21.
    Conrad KP, Colpoys MC. Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats. J Clin Invest. 1986;77:236–45.PubMedCrossRefGoogle Scholar
  22. 22.
    Danielson LA, Conrad KP. Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J Clin Invest. 1995;96:482–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Novak J, Reckelhoff J, Bumgarner L, et al. Reduced sensitivity of the renal circulation to angiotensin II in pregnant rats. Hypertension. 1997;30:580–4.PubMedGoogle Scholar
  24. 24.
    Ferreira VM, Gomes TS, Reis LA, et al. Receptor-induced dilatation in the systemic and intrarenal adaptation to pregnancy in rats. PLoS One. 2009;4:e4845.PubMedCrossRefGoogle Scholar
  25. 25.
    Sasser JM, Molnar M, Baylis C. Relaxin ameliorates hypertension and increases nitric oxide metabolite excretion in angiotensin II but not N(ω)-nitro-L-arginine methyl ester hypertensive rats. Hypertension. 2011;58:197–204.PubMedCrossRefGoogle Scholar
  26. 26.
    Danielson LA, Conrad KP. Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats. J Appl Physiol. 2003;95:1509–14.PubMedGoogle Scholar
  27. 27.
    Dschietzig T, Teichman S, Unemori E, et al. Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Card Fail. 2009;15:182–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Perna AM, Masini E, Nistri S, et al. Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model. FASEB J. 2005;19:1525–7.PubMedGoogle Scholar
  29. 29.
    Erikson MS, Unemori EN. Relaxin clinical trials in systemic sclerosis. In: Tregear GW, Ivell R, Bathgate RA, Wade JD, editors. Proceedings of the Third International Conference on Relaxin and Related Peptides. Dordrecht: Kluwer; 2001. p. 373–81.Google Scholar
  30. 30.
    Khanna D, Clements PJ, Furst DE, et al. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009;60:1102–11.PubMedCrossRefGoogle Scholar
  31. 31.
    • Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2008;14:321–9. The vascular actions of relaxin may have therapeutic indications for pathologies of pregnancy such as preeclampsia, as well as for disorders in the nonpregnant population, including heart failure. This work is important because it summarizes the rationale and evidence for the use of relaxin as a therapeutic agent in heart failure. PubMedCrossRefGoogle Scholar
  32. 32.
    Smith MC, Danielson LA, Conrad KP, Davison JM. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol. 2006;17:3192–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Jeyabalan A, Conrad KP. Renal physiology and pathophysiology in pregnancy. In: Schrier RW, editor. Renal and electrolyte disorders. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2010. p. 462–518.Google Scholar
  34. 34.
    Novak J, Danielson LA, Kerchner LJ, et al. Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J Clin Invest. 2001;107:1469–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Smith MC, Murdoch AP, Danielson LA, et al. Relaxin has a role in establishing a renal response in pregnancy. Fertil Steril. 2006;86:253–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Conrad KP. Possible mechanisms for changes in renal hemodynamics during pregnancy: studies from animal models. Am J Kidney Dis. 1987;9:253–9.PubMedGoogle Scholar
  37. 37.
    Rapoport RM, Murad F. Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res. 1983;52:352–7.PubMedGoogle Scholar
  38. 38.
    Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Conrad KP, Vernier KA. Plasma level, urinary excretion, and metabolic production of cGMP during gestation in rats. Am J Physiol. 1989;257:R847–53.PubMedGoogle Scholar
  40. 40.
    Conrad KP, Joffe GM, Kruszyna H, et al. Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 1993;7:566–71.PubMedGoogle Scholar
  41. 41.
    Gellai M, Fletcher T, Pullen M, Nambi P. Evidence for the existence of endothelin-B receptor subtypes and their physiological roles in the rat. Am J Physiol. 1996;271:R254–261.PubMedGoogle Scholar
  42. 42.
    Conrad KP, Gandley RE, Ogawa T, et al. Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. Am J Physiol. 1999;276:F767–76.PubMedGoogle Scholar
  43. 43.
    Alexander BT, Miller MT, Kassab S, et al. Differential expression of renal nitric oxide synthase isoforms during pregnancy in rats. Hypertension. 1999;33:435–9.PubMedGoogle Scholar
  44. 44.
    Novak J, Rajakumar A, Miles TM, Conrad KP. Nitric oxide synthase isoforms in the rat kidney during pregnancy. J Soc Gynecol Investig. 2004;11:280–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith CA, Santymire B, Erdely A, et al. Renal nitric oxide production in rat pregnancy: role of constitutive nitric oxide synthases. Am J Physiol Renal Physiol. 2010;299:F830–836.PubMedCrossRefGoogle Scholar
  46. 46.
    Kerchner LJ, Novak J, Hanley-Yanez K, et al. Evidence against the hypothesis that endothelial endothelin B receptor expression is regulated by relaxin and pregnancy. Endocrinol. 2005;146:2791–7.CrossRefGoogle Scholar
  47. 47.
    Dschietzig T, Bartsch C, Richter C, et al. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res. 2003;92:32–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Jeyabalan A, Novak J, Danielson LA, et al. Essential role for vascular gelatinase activity in relaxin-induced renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small arteries. Circ Res. 2003;93:1249–57.PubMedCrossRefGoogle Scholar
  49. 49.
    Unemori EN, Pickford LB, Salles AL, et al. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest. 1996;98:2739–45.PubMedCrossRefGoogle Scholar
  50. 50.
    Palejwala S, Stein DE, Weiss G, et al. Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology. 2001;142:3405–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Unemori EN, Amento EP. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem. 1990;265:10681–5.PubMedGoogle Scholar
  52. 52.
    Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999;85:906–11.PubMedGoogle Scholar
  53. 53.
    Fernandez-Patron C, Radomski MW, Davidge ST. Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries. Am J Physiol Heart Circ Physiol. 2000;278:H1473–1479.PubMedGoogle Scholar
  54. 54.
    Koivunen E, Arap W, Valtanen H, et al. Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol. 1999;17:768–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Jeyabalan A, Kerchner LJ, Fisher MC, et al. Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats. J Appl Physiol. 2006;100:1955–63.PubMedCrossRefGoogle Scholar
  56. 56.
    Kelly BA, Bond BC, Poston L. Aortic adaptation to pregnancy: elevated expression of matrix metalloproteinases-2 and −3 in rat gestation. Mol Hum Reprod. 2004;10:331–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Danielson LA, Welford A, Harris A. Relaxin improves renal function and histology in aging Munich Wistar rats. J Am Soc Nephrol. 2006;17:1325–33.PubMedCrossRefGoogle Scholar
  58. 58.
    van Eijndhoven HW, Janssen GM, Aardenburg R, et al. Mechanisms leading to increased vasodilator responses to calcitonin-gene-related peptide in mesenteric resistance arteries of early pregnant rats. J Vasc Res. 2008;45:350–6.PubMedCrossRefGoogle Scholar
  59. 59.
    • McGuane JT, Danielson LA, Debrah JE, et al. Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension. 2011;57:1151–60. This article is one of the latest in a series further elucidating the mechanisms of relaxin-induced “sustained” vasodilatory responses. It is significant because angiogenic growth factors are shown to be involved as molecular intermediates. The additional findings that “sustained” relaxin-induced vasodilation is observed in rat and mouse small renal arteries and human subcutaneous arteries, with similar underlying molecular mechanisms, suggest some degree of species conservation, perhaps underscoring the biologic importance of the hormone. PubMedCrossRefGoogle Scholar
  60. 60.
    Jeyabalan A, Novak J, Doty KD, et al. Vascular matrix metalloproteinase-9 mediates the inhibition of myogenic reactivity in small arteries isolated from rats after short-term administration of relaxin. Endocrinol. 2007;148:189–97.CrossRefGoogle Scholar
  61. 61.
    Novak J, Conrad KP. Small renal arteries isolated from ETB receptor deficient rats fail to exhibit the normal maternal adaptation to pregnancy [abstract]. FASEB J. 2004;18:32.Google Scholar
  62. 62.
    Debrah JE, Agoulnik A, Conrad KP. Changes in arterial function by chronic relaxin infusion are mediated by the leucine rich repeat G coupled Lgr7 receptor [abstract]. Reprod Sci. 2008;15(1 Suppl):217A.Google Scholar
  63. 63.
    Fisher C, MacLean M, Morecroft I, et al. Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? Circulation. 2002;106:292–5.PubMedCrossRefGoogle Scholar
  64. 64.
    • McGuane JT, Debrah JE, Sautina L, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology. 2011;152:2786–96. This publication investigates mechanisms of relaxin-induced “rapid” vasodilation. Once again, the finding that “rapid” relaxin-induced vasodilation is observed in rat and mouse small renal arteries and human subcutaneous arteries, and the similarity of the underlying molecular mechanisms (at least as tested in the rat and human) suggest some degree of species conservation, perhaps underscoring the biologic importance of the hormone. PubMedCrossRefGoogle Scholar
  65. 65.
    Novak J, Parry LJ, Matthews JE, et al. Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J. 2006;20:2352–62.PubMedCrossRefGoogle Scholar
  66. 66.
    McGuane JT, Parry LJ. Relaxin and the extracellular matrix: molecular mechanisms of action and implications for cardiovascular disease. Expert Rev Mol Med. 2005;7:1–18.PubMedCrossRefGoogle Scholar
  67. 67.
    Samuel CS. Relaxin: antifibrotic properties and effects in models of disease. Clin Med Res. 2005;3:241–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Samuel CS, Du XJ, Bathgate RA, Summers RJ. ‘Relaxin’ the stiffened heart and arteries: the therapeutic potential for relaxin in the treatment of cardiovascular disease. Pharmacol Ther. 2006;112:529–52.PubMedCrossRefGoogle Scholar
  69. 69.
    Lekgabe ED, Kiriazis H, Zhao C, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005;46:412–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Samuel CS, Hewitson TD, Zhang Y, Kelly DJ. Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy. Endocrinology. 2008;149:3286–93.PubMedCrossRefGoogle Scholar
  71. 71.
    Du XJ, Xu Q, Lekgabe E, et al. Reversal of cardiac fibrosis and related dysfunction by relaxin. Ann N Y Acad Sci. 2009;1160:278–84.PubMedCrossRefGoogle Scholar
  72. 72.
    Samuel CS, Cendrawan S, Gao XM, et al. Relaxin remodels fibrotic healing following myocardial infarction. Lab Invest. 2011;91:675–90.PubMedCrossRefGoogle Scholar
  73. 73.
    • Xu Q, Chakravorty A, Bathgate RA, et al. Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension. 2010;55:1260–6. This work provides evidence for relaxin’s antifibrotic properties in the setting of established vascular fibrosis (senescent spontaneously hypertensive rats) and demonstrates the beneficial functional effects of the reduction in vascular fibrosis: increased in vivo global arterial compliance and increased ex vivo passive vascular compliance. PubMedCrossRefGoogle Scholar
  74. 74.
    • Debrah DO, Debrah JE, Haney JL, et al. Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. J Appl Physiol. 2011;111:260–71. This work comprehensively evaluates the contributions of vascular geometric and compositional remodeling to the relaxin-induced increase in ex vivo passive vascular compliance.PubMedCrossRefGoogle Scholar
  75. 75.
    • Chan SL, Cipolla MJ. Relaxin causes selective outward remodeling of brain parenchymal arterioles via activation of peroxisome proliferator-activated receptor-γ. FASEB J. 2011;25:3229–39. This report is important because it implicates PPARγ as a molecular mediator of relaxin-induced arterial remodeling. PubMedCrossRefGoogle Scholar
  76. 76.
    Cipolla MJ, Sweet JG, Chan SL. Cerebral vascular adaptation to pregnancy and its role in the neurological complications of eclampsia. J Appl Physiol. 2011;110:329–39.PubMedCrossRefGoogle Scholar
  77. 77.
    Pagani M, Mirsky I, Baig H, et al. Effects of age on aortic pressure-diameter and elastic stiffness-stress relationships in unanesthetized sheep. Circ Res. 1979;44:420–9.PubMedGoogle Scholar
  78. 78.
    Gandley RE, Griggs KC, Conrad KP, McLaughlin MK. Intrinsic tone and passive mechanics of isolated renal arteries from virgin and late-pregnant rats. Am J Physiol. 1997;273:R22–27.PubMedGoogle Scholar
  79. 79.
    Reddy UM, Wapner RJ, Rebar RW, Tasca RJ. Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop. Obstet Gynecol. 2007;109:967–77.PubMedCrossRefGoogle Scholar
  80. 80.
    Davison JM, Homuth V, Jeyabalan A, et al. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol. 2004;15:2440–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Brecht A, Bartsch C, Baumann G, et al. Relaxin inhibits early steps in vascular inflammation. Regul Pept. 2011;166:76–82.PubMedCrossRefGoogle Scholar
  82. 82.
    Segal MS, Sautina L, Li S et al. Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice. Blood 2011; in press.Google Scholar
  83. 83.
    Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58.PubMedGoogle Scholar
  84. 84.
    Weiss G, Teichman S, Stewart D, et al. A randomized, double-blind, placebo-controlled trial of relaxin for cervical ripening in post-delivery date pregnancies. Ann N Y Acad Sci. 2009;1160:385–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Departments of Physiology and Functional Genomics, and of Obstetrics and Gynecology, and the D.H. Barron Reproductive and Perinatal Biology Research ProgramUniversity of FloridaGainesvilleUSA
  2. 2.Departments of Bioengineering and MedicineUniversity of PittsburghPittsburghUSA

Personalised recommendations