The human umbilical cord forms a connection between the placenta and the foetus. It is composed of two arteries and one vein surrounded by Wharton's jelly. Pre-eclampsia is accompanied by extensive remodeling of extracellular matrix of umbilical cord. Matrix metalloproteinases (MMPs) are engaged in degradation of extracellular matrix proteins and activation/inactivation of certain cytokines and enzymes. These enzymes will probably play a central role in the release of matrix-embedded cytokines and growth factors. MMP-2 (gelatinase A) is the main collagenolytic enzyme of both umbilical artery and vein. Other metalloproteinases are present in several times lower amounts. Reduced activity of collagen-degrading enzymes may be a factor, which enhances the accumulation of collagen and some other proteins in the pre-eclamptic umbilical cord tissues. It seems to be possible that similar alterations occur in other fetal blood vessels. It may result in an increase in peripheral resistance as well as an increase in the blood pressure in the fetal vascular system. Some observations suggest that the raised pressure may persist after birth. Pre-eclampsia may be a factor that evokes an initiation of hypertension in utero and its amplification through childhood and adulthood. 1. Structure of the Umbilical Cord The human umbilical cord forms a connection between the placenta and the foetus. It is composed of three blood vessels of different structure and function, one vein, which transports oxygenated and nutrition-rich blood from placenta to foetus, and two arteries, which transport deoxygenated blood and metabolic waste products from foetus to placenta. All these vessels are surrounded by Wharton’s jelly , which constitutes the major part of human umbilical cord and provides a thick protective mantle around vessels. Wharton’s jelly plays also an important role as a storage for some compounds, such as growth factors . The extracellular matrix (ECM) in the vascular wall contains many macromolecules (collagen, elastin, proteoglycans, and glycoproteins) necessary for the structural and functional properties of vessel wall . Proteolysis is a major process leading to changes in the ECM . 2. Remodeling of the Umbilical Cord in Pre-eclampsia 2.1. Umbilical Cord Artery It was found in our studies that pre-eclampsia is accompanied by an extensive remodelling of the ECM of the umbilical cord. The umbilical cord arteries (UCAs) of newborns delivered by mothers with pre-eclampsia contain more than twice the amount of collagen and markedly less elastin in comparison to
L. Romanowicz, E. Bańkowski, S. Jaworski, and L. Chyczewski, “Glycosaminoglycans of umbilical cord arteries and their alterations in EPH-gestosis,” Folia Histochemica et Cytobiologica, vol. 32, no. 3, pp. 199–204, 1994.
L. Romanowicz, E. Bańkowski, Z. Galewska, and S. Jaworski, “Glycosaminoglycan-biosynthesis in the wall of the umbilical cord artery and its alteration in EPH-gestosis,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 72, no. 1, pp. 19–25, 1997.
L. Romanowicz, E. Bańkowski, and S. Jaworski, “The activities of some glycosaminoglycan-degrading enzymes in the wall of the umbilical cord artery and their alteration in edema, proteinuria, hypertension (EPH)-gestosis,” Clinical Chemistry and Laboratory Medicine, vol. 37, no. 4, pp. 417–421, 1999.
P. D. Wadhwa, C. Buss, S. Entringer, and J. M. Swanson, “Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms,” Seminars in Reproductive Medicine, vol. 27, no. 5, pp. 358–368, 2009.
E. Bańkowski, E. Pawlicka, and S. Jaworski, “Stimulation of collagen biosynthesis by the umbilical cord serum of newborns delivered by mothers with EPH-gestosis (preeclampsia),” Clinica Chimica Acta, vol. 302, no. 1-2, pp. 23–24, 2000.
Z. Galewska, E. Bańkowski, L. Romanowicz, and S. Jaworski, “EPH-gestosis (pre-eclampsia)-induced decrease of gelatinase activity may promote an accumulation of collagen in the umbilical cord artery,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 88, no. 2, pp. 189–195, 2000.
P. Anastasiadis, K. Avgidou, A. N. Anastasiadis, A. Kotini, N. Koutlaki, and P. Anninos, “Correlation between biomagnetic and Doppler findings of the uterine artery in normal and preeclamptic pregnancies,” Prenatal Diagnosis, vol. 25, no. 1, pp. 51–56, 2005.
G. J. Burton, A. W. Woods, E. Jauniaux, and J. C. P. Kingdom, “Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy,” Placenta, vol. 30, no. 6, pp. 473–482, 2009.
J. E. Bishop, S. Rhodes, G. J. Laurent, R. B. Low, and W. S. Stirewalt, “Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overload,” Cardiovascular Research, vol. 28, no. 10, pp. 1581–1585, 1994.
D. J. P. Barker, C. Osmond, J. Golding, D. Kuh, and M. E. J. Wadsworth, “Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease,” British Medical Journal, vol. 298, no. 6673, pp. 564–567, 1989.
L. Romanowicz and K. Sobolewski, “Extracellular matrix components of the wall of umbilical cord vein and their alterations in pre-eclampsia,” Journal of Perinatal Medicine, vol. 28, no. 2, pp. 140–146, 2000.
T. Gogiel, Z. Galewska, L. Romanowicz, S. Jaworski, and E. Bańkowski, “Pre-eclampsia-associated alterations in decorin, biglycan and versican of the umbilical cord vein wall,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 134, no. 1, pp. 51–56, 2007.
L. Romanowicz, E. Bańkowski, and S. Jaworski, “Electrophoretic and chromatographic patterns of glycosaminoglycans of the umbilical cord vessels and their alteration in EPH-gestosis,” Acta Biochimica Polonica, vol. 45, no. 3, pp. 805–809, 1998.
L. Romanowicz and S. Jaworski, “The activities of some glycosaminoglycan degrading enzymes in the wall of the umbilical cord vein and their alteration in EPH-gestosis,” Ginekologia Polska, vol. 70, no. 12, pp. 873–880, 1999 (Polish).
E. Bańkowski, K. Sobolewski, L. Romanowicz, L. Chyczewski, and S. Jaworski, “Collagen and glycosaminoglycans of Wharton's jelly and their alterations in EPH-gestosis,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 66, no. 2, pp. 109–117, 1996.
L. Romanowicz, E. Bańkowski, K. Sobolewski, and S. Jaworski, “Activities of some glycosaminoglycan-degrading enzymes in Wharton's jelly and their alteration in EPH-gestosis (pre-eclampsia),” Biology of the Neonate, vol. 76, no. 3, pp. 144–152, 1999.
Z. Galewska, L. Romanowicz, E. Bańkowski, and S. Jaworski, “Preeclampsia-associated decrease of potential collagenolytic and gelatinolytic activities in the wall of the umbilical cord vein,” International Journal of Biochemistry and Cell Biology, vol. 34, no. 1, pp. 24–32, 2002.
L. M. B. Andersson and M. J. Warburton, “Intracellular degradation of type I collagen and fibronectin in human lung fibroblasts: evidence against degradation in pre-lysosomal compartments,” Biochimica et Biophysica Acta, vol. 1268, no. 1, pp. 27–34, 1995.
V. Everts, E. Van Der Zee, L. Creemers, and W. Beertsen, “Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling,” Histochemical Journal, vol. 28, no. 4, pp. 229–245, 1996.
L. B. Creemers, I. D. C. Jansen, A. J. P. Docherty, J. J. Reynolds, W. Beertsen, and V. Everts, “Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue,” Matrix Biology, vol. 17, no. 1, pp. 35–46, 1998.
E. H. M. Kerkvliet, A. J. P. Docherty, W. Beertsen, and V. Everts, “Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase,” Matrix Biology, vol. 18, no. 4, pp. 373–380, 1999.
T. Ishii and N. Asuwa, “Collagen and elastin degradation by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase in aortic dissection,” Human Pathology, vol. 31, no. 6, pp. 640–646, 2000.
F. Endo, A. Tanoue, H. Nakai, A. Hata, Y. Indo, K. Titani, and I. Matsuda, “Primary structure and gene localization of human prolidase,” Journal of Biological Chemistry, vol. 264, no. 8, pp. 4476–4481, 1989.
S. H. Jackson, A. W. Dennis, and M. Greenberg, “Iminodipeptiduria: a genetic defect in recycling collagen; a method for determining prolidase in erythrocytes,” Canadian Medical Association Journal, vol. 113, no. 8, pp. 759–763, 1975.
K. Sobolewski, Z. Galewska, M. Wolańska, and S. Jaworski, “The activity of collagen-degrading enzymes of Wharton's jelly in EPH gestosis (Pre-Eclampsia),” Biology of the Neonate, vol. 80, no. 3, pp. 202–209, 2001.
J. Klein and F. A. Meyer, “Tissue structure and macromolecular diffusion in umbilical cord. Immobilization of endogenous hyaluronic acid,” Biochimica et Biophysica Acta, vol. 755, no. 3, pp. 400–411, 1983.
R. M. Senior, G. L. Griffin, C. J. Fliszar, S. D. Shapiro, G. I. Goldberg, and H. G. Welgus, “Human 92- and 72-kilodalton type IV collagenases are elastases,” Journal of Biological Chemistry, vol. 266, no. 12, pp. 7870–7875, 1991.
H. Birkedal-Hansen and R. E. Taylor, “Detergent-activation of latent collagenase and resolution of its component molecules,” Biochemical and Biophysical Research Communications, vol. 107, no. 4, pp. 1173–1178, 1982.
Z. Galewska, E. Bańkowski, L. Romanowicz, and S. Jaworski, “Pre-eclampsia (EPH-gestosis)-induced decrease of MMP-s content in the umbilical cord artery,” Clinica Chimica Acta, vol. 335, no. 1-2, pp. 109–115, 2003.
Z. Galewska, L. Romanowicz, T. Gogiel, S. Jaworski, and E. Bańkowski, “The inhibitory effect of preeclamptic umbilical cord blood serum on matrix metalloproteinase-1 in arterial slices incubated in vitro,” Pathobiology, vol. 73, no. 6, pp. 310–316, 2007.
S. M. Wilhelm, I. E. Collier, B. L. Marmer, A. Z. Eisen, G. A. Grant, and G. I. Goldberg, “SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages,” Journal of Biological Chemistry, vol. 264, no. 29, pp. 17213–17221, 1989.
R. T. Aimes and J. P. Quigley, “Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4 - and 1/4 -length fragments,” Journal of Biological Chemistry, vol. 270, no. 11, pp. 5872–5876, 1995.
Z. S. Zeng, W. P. Shu, A. M. Cohen, and J. G. Guillem, “Matrix metalloproteinase-7 expression in colorectal cancer liver metastases: evidence for involvement of MMP-7 activation in human cancer metastases,” Clinical Cancer Research, vol. 8, no. 1, pp. 144–148, 2002.
D. Godin, E. Ivan, C. Johnson, R. Magid, and Z. S. Galis, “Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model,” Circulation, vol. 102, no. 23, pp. 2861–2866, 2000.
H. I. Park, J. Ni, F. E. Gerkema, D. Liu, V. E. Belozerov, and Q. X. A. Sang, “Identification and characterization of human endometase (matrix metalloproteinase-26) from endometrial tumor,” Journal of Biological Chemistry, vol. 275, no. 27, pp. 20540–20544, 2000.
Y. G. Zhao, AI. Z. Xiao, and AI. Z. Xiao, “Activation of pro-gelatinase B by endometase/matrilysin-2 promotes invasion of human prostate cancer cells,” Journal of Biological Chemistry, vol. 278, no. 17, pp. 15056–15064, 2003.
W. Hui, A. D. Rowan, and T. Cawston, “Insulin-like growth factor 1 blocks collagen release and down regulates matrix metalloproteinase-1, -3, -8, and -13 mRNA expression in bovine nasal cartilage stimulated with oncostatin M in combination with interleukin 1α,” Annals of the Rheumatic Diseases, vol. 60, no. 3, pp. 254–261, 2001.
TH. Chevalley, R. Rizzoli, D. Manen, J. Caverzasio, and J. P. Bonjour, “Arginine increases insulin-like growth factor-I production and collagen synthesis in osteoblast-like cells,” Bone, vol. 23, no. 2, pp. 103–109, 1998.
P. Gillery, A. Leperre, F. X. Maquart, and J. P. Borel, “Insulin-like growth factor-I (IGF-I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblasts,” Journal of Cellular Physiology, vol. 152, no. 2, pp. 389–396, 1992.
C. Telasky, E. E. Tredget, Q. Shen, M. R. Khorramizadeh, T. Iwashina, P. G. Scott, and A. Ghahary, “IFN-α2b suppresses the fibrogenic effects of insulin-like growth factor-1 in dermal fibroblasts,” Journal of Interferon and Cytokine Research, vol. 18, no. 8, pp. 571–577, 1998.
C. M. Law, A. W. Shiell, and A. W. Shiell, “Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age,” Circulation, vol. 105, no. 9, pp. 1088–1092, 2002.