title: PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary.
abstract: The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRβ) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRβ and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity.
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire, UK peter.a.hall@astrazeneca.com.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Hall
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Horner
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Zena
authors.initials: Z
authors.lastname: Wilson
authors.affiliation: AstraZeneca, Drug Safety and Metabolism, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Jaimini
authors.initials: J
authors.lastname: Reens
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Graham H P
authors.initials: GH
authors.lastname: Richmond
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Wedge
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003338:Corpus Luteum / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006651:Histocytochemistry; D010053:Ovary / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D020286:Pericytes / Q000187:drug effects*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: angiogenesis; corpus luteum; endothelial cell; ovary; pericyte; platelet-derived growth factor receptor (PDGFR); vascular endothelial growth factor receptor (VEGFR)