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 (PDGFRb) 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 PDGFRb 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.

Cleavage of proteoglycans, plasma proteins and the platelet-derived growth factor receptor in the hemorrhagic process induced by snake venom metalloproteinases

“…And concerning the crucial role of PDGFRβ–mediated interactions in recruitment of mural cells by newly formed vessels, genetic-induced disruption of PDGF-B or PDGFRβ leads to the development of microvascular leakage, lethal hemorrhage, and edema in late embryogenesis in mice 112 , 113 . Recently, using a rat model, Hall et al 114 showed that the use of specific PDGFRβ inhibitors resulted in pericyte depletion and hemorrhage into the corpus luteum of the ovary. In line with these findings, here we show that HF3 is able to cleave PDGFR (alpha and beta forms) and PDGF in vitro.…”

Effects of crenolanib, a nonselective inhibitor of PDGFR, in a mouse model of transient middle cerebral artery occlusion

“…Mice deficient in PDGFRβ completely lack brain pericytes and have increased BBB permeability that results in central nervous system microhemorrhages (Obermeier et al, 2013). Pharmacologic inhibition of PDGFRβ caused pericyte depletion and hemorrhage in rodents (Hall et al, 2016). Those findings indicate that blocking PDGFRα alone in the acute phase, without inhibiting the function of PDGFRβ, might provide an effective therapy for stroke.…”

Luteal toxicity evaluation in rats

“…Luteinization is comprised of two major processes: 1) termination of proliferation with rapid hypertrophy and differentiation of steroidogenic follicular cells (granulosa cells and theca cells) into luteal cells, and 2) the rapid growth of blood vessels (angiogenesis) into the previous granulosa layer of the follicle 2 . Vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF) play critical roles in luteal angiogenesis 2,10 .…”

“…If direct toxicity in the adrenal cortex is observed, CL should be carefully evaluated considering their effect on steroidogenesis and vice versa. Since angiogenesis is a critical process for luteinization, CL should be carefully evaluated if any changes resulting from anti-angiogenesis are suspected in various organs/tissues (e.g., epiphyseal growth plate thickening, adrenocortical necrosis/hemorrhage, and incisor tooth dental dysplasia) 10,32 . When test article-related histopathological changes in CL are observed, it is important to determine whether the changes are caused by a direct effect or by other associated factors.…”

“…For the mode of toxicity analysis, measurement of serum/plasma hormone levels, gene/protein expression analysis, special staining, or immunohistochemical analysis can provide pivotal information on a case-by-case or step-by-step basis 10,35 . Since CL is controlled by the upstream hypothalamicpituitary system, it is often difficult to explain the mode of toxicity in vivo.…”