Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

Abstract

The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

“…Neointimal formation after vessel injury is a complex process involving the proliferation and migration of VSMCs [21]. Apoptosis is also important in this process [34,35]. In this study, PD168077 significantly reduced the balloon injury caused neointimal hyperplasia in rat carotid artery.…”

Imatinib Ameliorated Retinal Neovascularization by Suppressing PDGFR-α and PDGFR-β

“…Additionally, anti-VEGF therapy could increase the expression of PDGFs, suggesting the activation of PDGFs/PDGFRs as a compensatory pathway in the absence of VEGF and the PDGFs/PDGFRs axis as a promising target for the treatment of angiogenic diseases [15,26,27]. Imatinib was reported to inhibit the expression and activation of PDGFRs in vitro and in vivo by targeting the ATP-binding site of tyrosine kinases of PDGFRs and inhibiting their biological effect [28,29]. In the present study, we found that imatinib could effectively ameliorate retinal angiogenesis by suppressing the expression and phosphorylation of PDGFRs in the OIR model, suggesting that imatinib may be a novel anti-angiogenesis drug used either alone or in combination with anti-VEGF therapy.…”

Disruption of the Bone Morphogenetic Protein Receptor 2 Pathway in Nitrofen‐Induced Congenital Diaphragmatic Hernia

“…Administration of the herbicide nitrofen (2,4-dichloro-p-nitrophenyl ether) to pregnant rats on day 9 (D9) of gestation induces PH and diaphragmatic defects in the offspring with striking similarities of the pathologies observed in human CDH (Beurskens et al, 2007;Corbett et al, 2012;Luong et al, 2011). It has been recently reported that the BMPR2 target proteins PDGF-BB and MCP-1 are significantly increased in nitrofeninduced CDH lungs (Chang et al, 2012;Gosemann et al, 2012).…”