CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation

Abstract

While anti-VEGF drugs are commonly used to inhibit pathological retinal and choroidal neovascularization, not all patients respond in an optimal manner. Mechanisms underpinning resistance to anti‑VEGF therapy include the upregulation of other proangiogenic factors. Therefore, therapeutic strategies that simultaneously target multiple growth factor signaling pathways would have significant value. Here, we show that Ca 2+ /calmodulin-dependent kinase II (CAMKII) mediates the angiogenic actions of a range of growth factors in human retinal endothelial cells and that this kinase acts as a key nodal point for the activation of several signal transduction cascades that are known to play a critical role in growth factor–induced angiogenesis. We also demonstrate that endothelial CAMKIIγ and -δ isoforms differentially regulate the angiogenic effects of different growth factors and that genetic deletion of these isoforms suppresses pathological retinal and choroidal neovascularization in vivo. Our studies suggest that CAMKII could provide a novel and efficacious target to inhibit multiple angiogenic signaling pathways for the treatment of vasoproliferative diseases of the eye. CAMKIIγ represents a particularly promising target, as deletion of this isoform inhibited pathological neovascularization, while enhancing reparative angiogenesis in the ischemic retina.

Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

“…Our work represents the first to link the Epac/CaMKII pathway to neuronal damage, particularly in the context of experimental glaucoma. This study, together with studies showing that CaMKII mediates retinal neuronal and vascular injury in diabetic retinopathy and is involved in growth factor-induced retinal and choroidal neovascularization (Ashraf et al, 2019;Kim et al, 2010Kim et al, , 2011Li et al, 2015), highlights the potential value of Epac1/CaMKII inhibition in treating a variety of retinopathies. Of note, an interesting quality of Epac signaling has been compartmentalization of the protein.…”

Endothelial Ca2+ Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel

“…Following the increase in [Ca 2+ ] i , multiple Ca 2+ -dependent decoders translate endothelial Ca 2+ signals into a pro-angiogenic outcome. These include, but are not limited to (Figure 2, Figure 3 and Figure 4): ERK 1/2 [77,104,219], PI3K/Akt [37,104,177], Ca 2+ /CaM-dependent protein kinase II (CaMKII) [220,221], calpain [222], myosin light chain kinase (MLCK) [25,223], Pyk2 [59,224], eNOS [73,104,225,226], and the transcription factors cAMP responsive element binding protein (CREB), nuclear factor of activated T-cells (NFAT) and nuclear factor kappa enhancer binding protein (NF-κB) [25,45,58,227,228,229]. VEGF has been the most frequent growth factor exploited to investigate how endothelial Ca 2+ signaling regulates angiogenesis [24].…”

“…Early work showed that CaMKII mediates VEGF-induced proliferation, migration, tubulogenesis and sprout formation in BREC [170]. Accordingly, a subsequent report confirmed that bFGF, IGF-1, and hepatocyte growth factor (HGF) induce BREC to undergo in vitro angiogenesis by recruiting CaMKII [220]. Of note, CaMKII stimulates BREC by engaging intermediate kinases to phosphorylate multiple effectors, including Akt, JNK, Src and FAK [220].…”

“…Accordingly, a subsequent report confirmed that bFGF, IGF-1, and hepatocyte growth factor (HGF) induce BREC to undergo in vitro angiogenesis by recruiting CaMKII [220]. Of note, CaMKII stimulates BREC by engaging intermediate kinases to phosphorylate multiple effectors, including Akt, JNK, Src and FAK [220]. Finally, genetic deletion of CaMKIIγ and CaMKIIδ interferes with choroidal neovascularization and hypoxia-induced angiogenesis in vivo [220].…”

Involvement of TRPV1 and TRPV4 Channels in Retinal Angiogenesis

“…NV, avascular, and normal vascular areas were quantified as a percentage of the total retinal area using custom software developed in our laboratory (OIR Select for ImageJ). 32 The normal vascular area comprises vessels from the superficial, intermediate, and deep capillary plexuses of the retina.…”