Ranibizumab Is a Potential Prophylaxis for Proliferative Vitreoretinopathy, a Nonangiogenic Blinding Disease

Pennock, Steven; Kim, David; Mukai, Sonoyo; Kuhnle, Matthew; Chun, Dal; Matsubara, Joanne A.; Cui, Jing; Ma, Patrick; Maberley, David; Samad, Arif; Geest, R.J. van der; Oberstein, Sarit L.; Schlingemann, Reinier O.; Kazlauskas, Andrius

doi:10.1016/j.ajpath.2013.01.052

Cited by 48 publications

(47 citation statements)

References 54 publications

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“…On day 28, immediately prior to sacrifice, electroretinogram (ERG) analysis was performed as previously described (41). Following euthanasia, the eyes were enucleated, fixed in 10% formalin, and embedded in paraffin.…”

Section: Figmentioning

confidence: 99%

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

Lei

Qian

Lei

et al. 2015

Molecular and Cellular Biology

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) make profound contributions to both physiology and pathology. While it is widely believed that direct (PDGF-mediated) activation is the primary mode of activating PDGFRs, the discovery that they can also be activated indirectly begs the question of the relevance of the indirect mode of activating PDGFRs. In the context of a blinding eye disease, indirect activation of PDGFR␣ results in persistent signaling, which suppresses the level of p53 and thereby promotes viability of cells that drive pathogenesis. Under the same conditions, PDGFR␤ fails to undergo indirect activation. In this paper, we report that RasGAP (GTPase-activating protein of Ras) prevented indirect activation of PDGFR␤. RasGAP, which associates with PDGFR␤ but not PDGFR␣, reduced the level of mitochondrion-derived reactive oxygen species, which are required for enduring activation of PDGFRs. Furthermore, preventing PDGFR␤ from associating with RasGAP allowed it to signal enduringly and drive pathogenesis of a blinding eye disease. These results indicate a previously unappreciated role of RasGAP in antagonizing indirect activation of PDGFR␤, define the underlying mechanism, and raise the possibility that PDGFR␤-mediated diseases involve indirect activation of PDGFR␤.T he receptors for platelet-derived growth factor (PDGF) are essential for mouse development and are implicated in a variety of human diseases (1, 2). Furthermore, these observations are the basis for the consensus that, while there may be overlap in what the two PDGF receptors (PDGFRs), PDGFR␣ and PDGFR␤, are capable of, they also have nonredundant functions in physiology and pathology.Because the two PDGFRs engage nonidentical signaling events in acutely stimulated cultured cells (3), a plausible reason for the distinct phenotype of mice lacking pdgfra and/or pdgfrb (4, 5) relates to signaling. Characterization of mice that express chimeric receptors in which the cytoplasmic domains were interchanged indicated that PDGFR␤ was more capable than PDGFR␣. PDGFR␣/␤ chimeric mice had no phenotype, whereas PDGFR␤/␣ chimeric mice showed some of the defects seen in mice in which PDGFR␤ lacked a major portion of the cytoplasmic domain (6, 7). Thus, in the context of mouse embryogenesis, the two PDGFRs do not appear to trigger the same signaling events, and more specifically, PDGFR␤ does something that PDGFR␣ cannot.The disparity in signaling events between the two PDGFRs that is germane to this report involves RasGAP (GTPase-activating protein of Ras), which is recruited by PDGFR␤ but not PDGFR␣ (8-10). RasGAP promotes the inactivation of Ras (11-13). RasGAP is an SH2 domain-containing protein, and its association with PDGFR␤ is dependent on tyrosine phosphorylation of PDGFR␤ within a context that is preferred by the SH2 domains of RasGAP (14-19). PDGFR␣ does not interact with RasGAP because none of its phosphorylation sites are within such an amino acid motif (9,10,20).Consistent with the known function of RasGAP, PDGF stimu...

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Section: Figmentioning

confidence: 99%

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

Lei

Qian

Lei

et al. 2015

Molecular and Cellular Biology

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“…Figure 1A illustrates our recent discovery that VEGF promotes viability of cells by reducing the level of p53. VEGF accomplishes this by persistently activating monomeric PDGFR␣; this process is independent of VEGFRs and even proceeds in fibroblasts, which express little few any VEGFRs (12,13,22). Although these discoveries were made in the context of a blinding eye disease, we speculated that this VEGF-driven survival mechanism was also relevant to physiology.…”

Section: Resultsmentioning

confidence: 99%

“…Attempts to identify which non-PDGFs are responsible for indirectly activating PDGFR␣ led to the discovery of a hierarchy among the three classes of growth factors that engage PDGFR␣ (12,13). These three classes of growth factors include PDGFs (direct activators), non-PDGFs (indirect activators), and vascular endothelial cell growth factor A (VEGF), which competitively antagonizes PDGF-dependent activation of PDGFR␣ (14).…”

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confidence: 99%

Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor α To Promote Viability of Cells Enduring Hypoxia

Pennock

Kim

Kazlauskas

2016

Molecular and Cellular Biology

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Vascular endothelial cell growth factor A (VEGF) is a biologically and therapeutically important growth factor because it promotes angiogenesis in response to hypoxia, which underlies a wide variety of both physiological and pathological settings. We report here that both VEGF receptor 2 (VEGFR2)-positive and -negative cells depended on VEGF to endure hypoxia. VEGF enhanced the viability of platelet-derived growth factor receptor ␣ (PDGFR␣)-positive and VEGFR2-negative cells by enabling indirect activation of PDGFR␣, thereby reducing the level of p53. We conclude that the breadth of VEGF's influence extends beyond VEGFR-positive cells and propose a plausible mechanistic explanation of this phenomenon. Receptor tyrosine kinases (RTKs) govern many biological processes. They can be activated in multiple ways, including by their cognate ligands (direct activation), and indirectly, which has also been called transactivation. For instance, circulating autoantibodies and ligands of G protein coupled receptor induce tyrosine phosphorylation of platelet-derived growth factor receptors (PDGFRs) (1-10).In the context of a blinding eye disease called proliferative vitreoretinopathy, indirect activation of PDGFR␣ drives pathogenesis in experimental animals and is associated with this disease in patients (11). Disease initiation involves mislocalization of cells into the vitreous of the eye, whereupon such cells are exposed to a plethora of growth factors that selectively and enduringly activate PDGFR␣ and thereby promotes the viability of the mislocalized cells by reducing the level of p53. The vitreal growth factors that are responsible for indirectly activating PDGFR␣ are outside the PDGF family and hence called non-PDGFs.Attempts to identify which non-PDGFs are responsible for indirectly activating PDGFR␣ led to the discovery of a hierarchy among the three classes of growth factors that engage PDGFR␣ (12, 13). These three classes of growth factors include PDGFs (direct activators), non-PDGFs (indirect activators), and vascular endothelial cell growth factor A (VEGF), which competitively antagonizes PDGF-dependent activation of PDGFR␣ (14). The hierarchy between these three classes of growth factors is shown in Fig. 1A and termed the VEGF/PDGF/non-PDGF paradigm. This diagram illustrates how VEGF promotes the survival of cells via PDGFR␣.As mentioned above, the VEGF/PDGF/non-PDGF paradigm was discovered in a pathological context. In the course of testing its relevance in a physiological setting, which is the focus of this report, the following novel discoveries were made. VEGF promoted survival of VEGF receptor 2 (VEGFR2)-negative cells (such as fibroblasts) during hypoxia in vitro, ex vivo, and in vivo. Furthermore, the VEGF/PDGF/non-PDGF paradigm was a plausible explanation for this phenomenon. MATERIALS AND METHODSCell culture. Primary mouse embryonic fibroblasts (MEFs) were obtained from American Type Culture Collection (Manassas, VA) at passage 2, used between passages 3 to 7, and maintained in high-glucose-containing ...

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“…2 Recent studies have shown a strong role for growth factors in the pathogenesis of proliferative vitreoretinopathy (PVR). 3,4 Vascular endothelial cell growth factor (VEGF) A has been reported to be able to activate the platelet-derived growth factor (PDGF) receptor a, a receptor tyrosine kinase that is key to pathogenesis of PVR. 3 Interestingly, Pennock et al 4 reported that ranibizumab protected the rabbits from developing PVR.…”

mentioning

confidence: 99%

“…3,4 Vascular endothelial cell growth factor (VEGF) A has been reported to be able to activate the platelet-derived growth factor (PDGF) receptor a, a receptor tyrosine kinase that is key to pathogenesis of PVR. 3 Interestingly, Pennock et al 4 reported that ranibizumab protected the rabbits from developing PVR. In contrast to these findings, our results showed that intrasilicone injection of bevacizumab does not eliminate the risk of subsequent PVR and may be associated with subretinal proliferation.…”

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confidence: 99%

Proliferative vitreoretinopathy and antivascular endothelial growth factor treatment

Falavarjani

Modarres

2014

Eye

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Ranibizumab Is a Potential Prophylaxis for Proliferative Vitreoretinopathy, a Nonangiogenic Blinding Disease

Cited by 48 publications

References 54 publications

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor α To Promote Viability of Cells Enduring Hypoxia

Proliferative vitreoretinopathy and antivascular endothelial growth factor treatment

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