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

Abstract

Background/Aims: Platelet-derived growth factors (PDGFs) have emerged as pivotal in pathological angiogenesis, which is a hallmark of various tumors and retinal diseases. Here we evaluated the anti-angiogenic effect of imatinib, an inhibitor of PDGF receptors α and β (PDGFR-α and -β), in retinal neovascularization using an oxygen-induced retinopathy (OIR) model. Methods: The OIR model was established and given imatinib or vehicle treatments daily from P12 to P16. At the peak of angiogenesis at P17, the neovascularization area was quantified on retinal whole-mounts with isolectin B4 staining. Immunofluorescence staining and western blots were used to determine the effect of imatinib on different vascular cells and the pathway molecules involved. Results: Imatinib effectively suppressed pathological angiogenesis in OIR mice and reduced the number of all three types of vascular cells, including endothelial cells, pericytes, and smooth muscle cells. Moreover, the expression and activation of PDGFR-α and -β were inhibited by imatinib. The imatinib-treated OIR mice presented with reduced expression of other potent pro-angiogenic factors such as VEGF and FGF2. No obvious retinal or systemic side effects were observed in the imatinib treatment group. Conclusions: Imatinib appears to be safe and effective in suppressing retinal neovascularization. Targeting PDGFs/PDGFRs may also be important for anti-angiogenic treatment and offer a viable alternative treatment for retinal angiogenic diseases.

Imatinib Sets Pericyte Mosaic in the Retina

“…Imatinib, as a potent PDGFR, tyrosine kinase and KIT inhibitor has been successfully used in treating cancer, and thus could provide an alternative treatment strategy in neurovascular diseases. It has also been shown previously that using imatinib as a PDGFR inhibitor during retinal development after OIR (oxygen-induced retinal) neovascularization successfully ameliorated retinal degeneration in the developing retina [24]. Using genetic PDGFR-knockouts also showed PC depletion, leading to aberrant blood flow [39], albeit that such genetic modifications could be difficult in humans.…”

“…NG2 is a more suitable marker for PC morphological assessment and counting, as the somata of the cells are evenly visible and can be found in the inner retina in three separate layers [6,7,22] (Figure 1a,b and Figure 2). Imatinib has potentially been used as a selective cancer treatment, acting through multiple signaling pathways [23][24][25]. It is a BCR-ABL tyrosine kinase inhibitor and platelet-derived growth factor receptor (PDGFR) and KIT inhibitor, and thus induces apoptosis by inhibiting PDGFs but not insulin-induced PI 3-kinase/Akt survival signaling [26].…”

“…Pharmacologic intervention with PDGFR-β inhibitors, such as imatinib, has shown significant effects in attenuating angiogenesis by reducing PC density. In addition, imatinib has been shown to successfully inhibit retinal neovascularization in oxygen-induced retinopathy in development by reducing the number of vascular cells, including PCs [24,28]. However, targeting PDGFR by imatinib administration in the adult retina has not been extensively evaluated as a potential model for pathological PC loss.…”

Role of platelet-derived growth factor in type II diabetes mellitus and its complications

“…Accordingly, anti-PDGF-BB drugs may be applied to DR treatment by reducing retinal neovascularization. 49 Interestingly, PDGF-BB can also prevent pericyte cellular apoptosis through the activation of PDGF-BB/ PDGFR-β-induced Akt or ERK phosphorylation, which increases DNA synthesis under normal glucose concentration in the retina. Pericyte apoptosis in DR caused by hyperglycaemia is related to the inhibition of survival effects of PDGF-BB/PDGFR-β downstream signalling via the activation of PKC δ-p38 MAPK-SHP-1 pathway.…”

“…Besides, imatinib, an inhibitor targeting PDGFR-α and PDGFR-β, was proved to reduce retinal neovascularization in the oxygeninduced retinopathy (OIR) mouse model. 49 However, PDGF-BB is needed for the prevention of pericyte cellular apoptosis. This protective function is inhibited by the high concentration of blood glucose.…”