title: Matrix metalloproteinase inhibition influences aspects of photoperiod stimulated ovarian recrudescence in Siberian hamsters.
abstract: Blocking matrix metalloproteinase (MMP) activity in vivo with inhibitor GM6001 impedes photostimulated ovarian recrudescence in photoregressed Siberian hamsters. Since direct and indirect effects of MMPs influence a myriad of ovarian functions, we investigated the effect of in vivo MMP inhibition during recrudescence on ovarian mRNA expression of steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD), Cyp19a1 aromatase, epidermal growth factor receptor (EGFR), amphiregulin (Areg), estrogen receptors (Esr1 and Esr2), tissue inhibitors of MMPs (TIMP-1,-2,-3), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor A (VEGFA), its receptor VEGFR-2, and angiopoietin-2 (Ang-2). Female Siberian hamsters were randomly assigned to one of four photoperiod groups: stimulatory long (LD) or inhibitory short (SD) photoperiods, or transferred from SD to LD for 2 weeks (post-transfer, PT). Half of the PT hamsters were injected (ip) daily with GM6001 (PTG). SD exposure reduced ovarian StAR, 3β-HSD, Cyp19a1, Esr1, Esr2, TIMPs 2-3, PCNA, VEGFR-2 and Ang-2 mRNA expression (p<0.05), and 2 weeks of photostimulation restored mRNA expression of 3β-HSD and PCNA and increased Areg and VEGFA mRNA expression in the PT group. GM6001 treatment during photostimulation (PTG) increased TIMP-1, -2 and -3 and PCNA mRNA, but inhibited Areg mRNA expression compared to PT. Neither photoperiod nor GM6001 altered EGFR expression. Results of this study suggest that in vivo inhibition of MMP activity by GM6001 may impede ovarian recrudescence, particularly follicular growth, in two ways: (1) directly by partially inhibiting the release of EGFR ligands like Areg, thereby potentially affecting EGFR activation and its downstream pathway, and (2) indirectly by its effect on TIMPs which themselves can affect proliferation, angiogenesis and follicular growth.
authors.affiliation: Reproductive Biology Group, Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840, United States.
authors.forename: Asha
authors.initials: A
authors.lastname: Shahed
authors.affiliation: Reproductive Biology Group, Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840, United States.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Simmons
authors.affiliation: Reproductive Biology Group, Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840, United States.
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Featherstone
authors.affiliation: Reproductive Biology Group, Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840, United States. Electronic address: kelly.young@csulb.edu.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Young
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D006224:Cricetinae; D004151:Dipeptides / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017440:Photoperiod; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D015415:Biomarkers; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D000098682:Steroidogenic Acute Regulatory Protein; D019716:Tissue Inhibitor of Metalloproteinase-2; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D001141:Aromatase; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases
keywords: EGFR; MMP; Photoperiod; Recrudescence; TIMPs