[en] In the corpus luteum (CL), blood vessels develop, stabilize, and regress. This process depends on the ratio of pro-and antiangiogenic factors, which change during the ovarian cycle. The present study focuses on the possible roles of 23,000 (23K) prolactin (PRL) in the bovine CL and its antiangiogenic NH2-terminal fragments after extracellular cleavage by cathepsin D (Cath D). PRL RNA and protein were demonstrated in the CL tissue, in luteal endothelial cells, and in steroidogenic cells. Cath D was detected in CL tissue, cell extracts, and corresponding cell supernatants. In the intact CL, 23K PRL levels decreased gradually, whereas Cath D levels concomitantly increased between early and late luteal stages. In vitro, PRL cleavage occurred in the presence of acidified homogenates of CL tissue, cells, and corresponding cell supernatants. Similar fragments were obtained with purified Cath D, and their appearance was inhibited by pepstatin A. The aspartic protease specific substrate MOCAc-GKPILF similar to FRLK(Dnp)-D-R-NH2 was cleaved by CL cell supernatants, providing further evidence for Cath D activity. The 16,000 PRL inhibited proliferation of luteal endothelial cells accompanied by an increase in cleaved caspase-3. In conclusion, 1) the bovine CL is able to produce PRL and to process it into antiangiogenic fragments by Cath D activity and 2) PRL cleavage might mediate angioregression during luteolysis.
Ahlemeyer B, Klumpp S, Krieglstein J. Release of cytochrome c into the extracellular space contributes to neuronal apoptosis induced by staurosporine. Brain Res 934: 107-116, 2002.
Arakaki N, Nagao T, Niki R, Toyofuku A, Tanaka H, Kuramoto Y, Emoto Y, Shibata H, Magota K, Higuti T. Possible role of cell surface H+ -ATP synthase in the extracellular ATP synthesis and proliferation of human umbilical vein endothelial cells. Mol Cancer Res 1: 931-939, 2003.
Bachelot A, Binart N. Corpus luteum development: lessons from genetic models in mice. Curr Top Dev Biol 68: 49-84, 2005.
Baldocchi RA, Tan L, King DS, Nicoll CS. Mass spectrometric analysis of the fragments produced by cleavage and reduction of rat prolactin: evidence that the cleaving enzyme is cathepsin D. Endocrinology 133: 935-938, 1993.
Baldocchi RA, Tan L, Nicoll CS. Processing of rat prolactin by rat tissue explants and serum in vitro. Endocrinology 130: 1653-1659, 1992.
Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 17: 639-669, 1996.
Berchem G, Glondu M, Gleizes M, Brouillet JP, Vignon F, Garcia M, Liaudet-Coopman E. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene 21: 5951-5955, 2002.
Bevers MM, Dieleman SJ, Kruip TA. [The role of prolactin during the estrus cycle of cattle.] Tijdschr Diergeneeskd 113: 1227-1236, 1988.
Boland NI, Humpherson PG, Leese HJ, Gosden RG. The effect of glucose metabolism on murine follicle development and steroidogenesis in vitro. Hum Reprod 9: 617-623, 1994.
Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19: 225-268, 1998.
Boonyaprakob U, Gadsby JE, Hedgpeth V, Routh PA, Almond GW. Expression and localization of hypoxia inducible factor-1α mRNA in the porcine ovary. Can J Vet Res 69: 215-222, 2005.
Briozzo P, Morisset M, Capony F, Rougeot C, Rochefort H. In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. Cancer Res 48: 3688-3692, 1988.
Carini R, Castino R, De Cesaris MG, Splendore R, Demoz M, Albano E, Isidoro C. Preconditioning-induced cytoprotection in hepatocytes requires Ca2+-dependent exocytosis of lysosomes. J Cell Sci 117: 1065-1077, 2004.
Clapp C. Analysis of the proteolytic cleavage of prolactin by the mammary gland and liver of the rat: characterization of the cleaved and 16K forms. Endocrinology 121: 2055-2064, 1987.
Clapp C, Lopez-Gomez FJ, Nava G, Corbacho A, Torner L, Macotela Y, Duenas Z, Ochoa A, Noris G, Acosta E, Garay E, Martinez de la Escalera G. Expression of prolactin mRNA and of prolactin-like proteins in endothelial cells: evidence for autocrine effects. J Endocrinol 158: 137-144, 1998.
Compton MM, Witorsch RJ. Proteolytic degradation and modification of rat prolactin by subcellular fractions of the rat ventral prostate gland. Endocrinology 115: 476-484, 1984.
Corbacho AM, Martinez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. J Endocrinol 173: 219-238, 2002.
Crichton EG, Hoyer PB, Krutzsch PH. Cellular composition and steroidogenic capacity of the ovary of Macrotus californicus (Chiroptera: Phyllostomatidae) during and after delayed embryonic development. Cell Tissue Res 260: 355-366, 1990.
Davis JS, Rueda BR, Spanel-Borowski K. Microvascular endothelial cells of the corpus luteum. Reprod Biol Endocrinol 1: 89, 2003.
Decker RS, Poole AR, Crie JS, Dingle JT, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. II. Immunohistochemical and biochemical changes in cathepsin D. Am J Pathol 98: 445-456, 1980.
Decker RS, Poole AR, Griffin EE, Dingle JT, Wildenthal K. Altered distribution of lysosomal cathepsin D in ischemic myocardium. J Clin Invest 59: 911-921, 1977.
Delbeke D, Kojima I, Dannies PS. Comparison of patterns of prolactin release in GH4C1 cells and primary pituitary cultures. Mol Cell Endocrinol 43: 15-22, 1985.
Dingle JT, Hay MF, Moor RM. Lysosomal function in the corpus luteum of the sheep. J Endocrinol 40: 325-336, 1968.
Duenas Z, Rivera JC, Quiroz-Mercado H, Aranda J, Macotela Y, Montes de Oca P, Lopez-Barrera F, Nava G, Guerrero JL, Suarez A, De Regil M, Martinez de la Escalera G, Clapp C. Prolactin in eyes of patients with retinopathy of prematurity: implications for vascular regression. Invest Ophthalmol Vis Sci 45: 2049-2055, 2004.
Einspanier R, Pitzel L, Wuttke W, Hagendorff G, Preuss KD, Kardalinou E, Scheit KH. Demonstration of mRNAs for oxytocin and prolactin in porcine granulosa and luteal cells. Effects of these hormones on progesterone secretion in vitro. FEBS Lett 204: 37-40, 1986.
Fischer B, Kunzel W, Kleinstein J, Gips H. Oxygen tension in follicular fluid falls with follicle maturation. Eur J Obstet Gynecol Reprod Biol 43: 39-43, 1992.
Follo C, Castino R, Nicotra G, Trincheri NF, Isidoro C. Folding, activity and targeting of mutated human cathepsin D that cannot be processed into the double-chain form. Int J Biochem Cell Biol 39: 638-649, 2007.
Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 80: 1523-1631, 2000.
Gafvels M, Selstam G, Damber JE. Influence of oxygen tension and substrates on basal and luteinizing hormone stimulated progesterone production and energy metabolism by isolated corpora lutea of adult pseudopregnant rats. Acta Physiol Scand 130: 475-482, 1987.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891-899, 2004.
Gaytan F, Morales C, Bellido C, Aguilar E, Sanchez-Criado JE. Role of prolactin in the regulation of macrophages and in the proliferative activity of vascular cells in newly formed and regressing rat corpora lutea. Biol Reprod 57: 478-486, 1997.
Gieselmann V, Pohlmann R, Hasilik A, Von Figura K. Biosynthesis and transport of cathepsin D in cultured human fibroblasts. J Cell Biol 97: 1-5, 1983.
Girsh E, Wang W, Mamluk R, Arditi F, Friedman A, Milvae RA, Meidan R. Regulation of endothelin-1 expression in the bovine corpus luteum: elevation by prostaglandin F 2α. Endocrinology 137: 5191-5196, 1996.
Glondu M, Coopman P, Laurent-Matha V, Garcia M, Rochefort H, Liaudet-Coopman E. A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells. Oncogene 20: 6920-6929, 2001.
Gosden RG, Byatt-Smith JG. Oxygen concentration gradient across the ovarian follicular epithelium: model, predictions and implications. Hum Reprod 1: 65-68, 1986.
Griffiths JR. Are cancer cells acidic? Br J Cancer 64: 425-427, 1991.
Grosdemouge I, Bachelot A, Lucas A, Baran N, Kelly PA, Binart N. Effects of deletion of the prolactin receptor on ovarian gene expression. Reprod Biol Endocrinol 1: 12, 2003.
Hakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, Pentikainen MO. Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 23: 1430-1436, 2003.
Hasilik A, von Figura K, Conzelmann E, Nehrkorn H, Sandhoff K. Lysosomal enzyme precursors in human fibroblasts. Activation of cathepsin D precursor in vitro and activity of beta-hexosaminidase A precursor towards ganglioside GM2. Eur J Biochem 125: 317-321, 1982.
Hill RP, De Jaeger K, Jang A, Cairns R. pH, hypoxia and metastasis. Novartis Found Symp 240: 154-165; discussion 165-158, 2001.
Ireland JJ, Murphee RL, Coulson PB. Accuracy of predicting stages of bovine estrous cycle by gross appearance of the corpus luteum. J Dairy Sci 63: 155-160, 1980.
Ito H, Miyazaki M, Nishimura F, Nakajima N. Secretion of extracellular matrix (fibronectin), growth factor (transforming growth factor β) and protease (cathepsin D) by hepatoma cells. Oncology 58: 261-270, 2000.
Johansson AC, Steen H, Ollinger K, Roberg K. Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine. Cell Death Differ 10: 1253-1259, 2003.
Kagedal K, Johansson U, Ollinger K. The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. FASEB J 15: 1592-1594, 2001.
Kajta M, Lason W, Kupiec T. Effects of estrone on N-methyl-D-aspartic acid- and staurosporine-induced changes in caspase-3-like protease activity and lactate dehydrogenase-release: time- and tissue-dependent effects in neuronal primary cultures. Neuroscience 123: 515-526, 2004.
Khurana S, Liby K, Buckley AR, Ben-Jonathan N. Proteolysis of human prolactin: resistance to cathepsin D and formation of a nonangiostatic, C-terminal 16K fragment by thrombin. Endocrinology 140: 4127-4132, 1999.
Lahav M, Meidan R, Amsterdam A, Gebauer H, Lindner HR. Intracellular distribution of cathepsin D in rat corpora lutea in relation to reproductive state and the action of prostaglandin F2α and prolactin. J Endocrinol 75: 317-324, 1977.
Laurent-Matha V, Maruani-Herrmann S, Prebois C, Beaujouin M, Glondu M, Noel A, Alvarez-Gonzalez ML, Blacher S, Coopman P, Baghdiguian S, Gilles C, Loncarek J, Freiss G, Vignon F, Liaudet-Coopman E. Catalytically inactive human cathepsin D triggers fibroblast invasive growth. J Cell Biol 168: 489-499, 2005.
Lillie R, Ashburn L. Supersaturated solutions of fat stains in dilute isopropanol for the demonstration of acute fatty degeneration not shown by Herxheimer's technique. Arch Pathol 36: 432-441, 1943.
Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. J Cell Sci 117: 5155-5164, 2004.
Ludwig T, Griffiths G, Hoflack B. Distribution of newly synthesized lysosomal enzymes in the endocytic pathway of normal rat kidney cells. J Cell Biol 115: 1561-1572, 1991.
Macotela Y, Aguilar MB, Guzman-Morales J, Rivera JC, Zermeno C, Lopez-Barrera F, Nava G, Lavalle C, Martinez de la Escalera G, Clapp C. Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin. J Cell Sci 119: 1790-1800, 2006.
Modlich U, Kaup FJ, Augustin HG. Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. Lab Invest 74: 771-780, 1996.
Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi J, Naito S, Nozaki C, Iwanaga S, Kuwano M. Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. J Biol Chem 275: 38912-38920, 2000.
Neeman M, Abramovitch R, Schiffenbauer YS, Tempel C. Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle. Int J Exp Pathol 78: 57-70, 1997.
Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW. Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 80: 1-29, 2000.
Oksjoki S, Soderstrom M, Vuorio E, Anttila L. Differential expression patterns of cathepsins B, H, K, L and S in the mouse ovary. Mol Hum Reprod 7: 27-34, 2001.
O'Shea JD, Nightingale MG, Chamley WA. Changes in small blood vessels during cyclical luteal regression in sheep. Biol Reprod 17: 162-177, 1977.
Pain RH, Lah T, Turk V. Conformation and processing of cathepsin D. Biosci Rep 5: 957-967, 1985.
Paris N, Rentier-Delrue F, Defontaine A, Goffin V, Lebrun JJ, Mercier L, Martial JA. Bacterial production and purification of recombinant human prolactin. Biotechnol Appl Biochem 12: 436-449, 1990.
Payne AH, Downing JR, Wong KL. Luteinizing hormone receptors and testosterone synthesis in two distinct populations of Leydig cells. Endocrinology 106: 1424-1429, 1980.
Perchick GB, Jabbour HN. Cyclooxygenase-2 overexpression inhibits cathepsin D-mediated cleavage of plasminogen to the potent antiangiogenic factor angiostatin. Endocrinology 144: 5322-5328, 2003.
Picazo RA, Garcia Ruiz JP, Santiago Moreno J, Gonzalez de Bulnes A, Munoz J, Silvan G, Lorenzo PL, Illera JC. Cellular localization and changes in expression of prolactin receptor isoforms in sheep ovary throughout the estrous cycle. Reproduction 128: 545-553, 2004.
Piwnica D, Fernandez I, Binart N, Touraine P, Kelly PA, Goffin V. A new mechanism for prolactin (PRL) processing into 16K PRL by secreted cathepsin D. Mol Endocrinol 20: 3263-3278, 2006.
Piwnica D, Touraine P, Struman I, Tabruyn S, Bolbach G, Clapp C, Martial JA, Kelly PA, Goffin V. Cathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: study of their antiangiogenic properties and physiological relevance. Mol Endocrinol 18: 2522-2542, 2004.
Rall JH, Cranna EJ, Gevers W, Street B. Effects of three prostaglandin analogues on lysosomal enzyme activities and ultrastructural morphology of luteal cells in the chacma baboon. S Afr Med J 59: 633-637, 1981.
Richardson DW, Goldsmith LT, Pohl CR, Schallenberger E, Knobil E. The role of prolactin in the regulation of the primate corpus luteum. J Clin Endocrinol Metab 60: 501-504, 1985.
Ricken AM, Spanel-Borowski K, Saxer M, Huber PR. Cytokeratin expression in bovine corpora lutea. Histochem Cell Biol 103: 345-354, 1995.
Ricken AM, Traenkner A, Merkwitz C, Hummitzsch K, Grosche J, Spanel-Borowski K. The short prolactin receptor predominates in endothelial cells of micro- and macrovascular origin. J Vasc Res 44: 19-30, 2007.
Rojas JD, Sennoune SR, Maiti D, Martinez GM, Bakunts K, Wesson DE, Martinez-Zaguilan R. Plasmalemmal V-H(+)-ATPases regulate intracellular pH in human lung microvascular endothelial cells. Biochem Biophys Res Commun 320: 1123-1132, 2004.
Sakai H, Saku T, Kato Y, Yamamoto K. Quantitation and immunohistochemical localization of cathepsins E and D in rat tissues and blood cells. Biochim Biophys Acta 991: 367-375, 1989.
Scammell JG, Luck DN, Valentine DL, Smith M. Epitope mapping of monoclonal antibodies to bovine prolactin. Am J Physiol Endocrinol Metab 263: E520-E525, 1992.
Shibaya M, Murakami S, Tatsukawa Y, Skarzynski DJ, Acosta TJ, Okuda K. Bovine corpus luteum is an extrapituitary site of prolactin production. Mol Reprod Dev 73: 512-519, 2006.
Shirasuna K, Asaoka H, Acosta TJ, Wijayagunawardane MP, Matsui M, Ohtani M, Miyamoto A. Endothelin-1 within the corpus luteum during spontaneous luteolysis in the cow: local interaction with prostaglandin F 2α and angiotensin II. J Cardiovasc Pharmacol 44: S252-S255, 2004.
Skrzydlewska E, Sulkowska M, Koda M, Sulkowski S. Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J Gastroenterol 11: 1251-1266, 2005.
Smallbone K, Gavaghan DJ, Gatenby RA, Maini PK. The role of acidity in solid tumour growth and invasion. J Theor Biol 235: 476-484, 2005.
Spanel-Borowski K. Diversity of ultrastructure in different phenotypes of cultured microvessel endothelial cells isolated from bovine corpus luteum. Cell Tissue Res 266: 37-49, 1991.
Spanel-Borowski K, Ricken AM, Kress A, Huber PR. Isolation of granulosa-like cells from the bovine secretory corpus luteum and their characterization in long-term culture. Anat Rec 239: 269-279, 1994.
Spanel-Borowski K, van der Bosch J. Different phenotypes of cultured microvessel endothelial cells obtained from bovine corpus luteum. Study by light microscopy and by scanning electron microscopy (SEM). Cell Tissue Res 261: 35-47, 1990.
Stacy BD, Gemmell RT, Thorburn GD. Morphology of the corpus luteum in the sheep during regression induced by prostaglandin F2α. Biol Reprod 14: 280-291, 1976.
Struman I, Bentzien F, Lee H, Mainfroid V, D'Angelo G, Goffin V, Weiner RI, Martial JA. Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis. Proc Natl Acad Sci USA 96: 1246-1251, 1999.
Sudhakaran PR, Kurup PA. Vitamin A and lysosomal stability in rat liver. J Nutr 104: 1466-1475, 1974.
Swallow CJ, Grinstein S, Rotstein OD. A vacuolar type H +-ATPase regulates cytoplasmic pH in murine macrophages. J Biol Chem 265: 7645-7654, 1990.
Tabruyn SP, Nguyen NQ, Cornet AM, Martial JA, Struman I. The antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G0-G1 and the G2-M phases. Mol Endocrinol 19: 1932-1942, 2005.
Tabruyn SP, Sorlet CM, Rentier-Delrue F, Bours V, Weiner RI, Martial JA, Struman I. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-κB. Mol Endocrinol 17: 1815-1823, 2003.
Tatnell PJ, Fowler SD, Bur D, Lees WE, Kay J. Cathepsin E. The best laid plans of mice and men. Adv Exp Med Biol 436: 147-152, 1998.
Uchiyama Y. Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol 64: 233-246, 2001.
Van der Stappen JW, Williams AC, Maciewicz RA, Paraskeva C. Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D. Int J Cancer 67: 547-554, 1996.
Vetvicka V, Benes P, Fusek M. Procathepsin D in breast cancer: what do we know? Effects of ribozymes and other inhibitors. Cancer Gene Ther 9: 854-863, 2002.
Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L. Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Am J Pathol 162: 1183-1190, 2003.
Yamamoto K. Cathepsin E and cathepsin D: biosynthesis, processing and subcellular location. Adv Exp Med Biol 362: 223-229, 1995.
Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA 102: 13807-13812, 2005.
Yasuda Y, Kageyama T, Akamine A, Shibata M, Kominami E, Uchiyama Y, Yamamoto K. Characterization of new fluorogenic substrates for the rapid and sensitive assay of cathepsin E and cathepsin D. J Biochem (Tokyo) 125: 1137-1143, 1999.
Zaidi N, Herrmann T, Baechle D, Schleicher S, Gogel J, Driessen C, Voelter W, Kalbacher H. A new approach for distinguishing cathepsin E and D activity in antigen-processing organelles. FEBS J 274: 3138-3149, 2007.