Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina

Sun, Jingfang; Hopkins, Benjamin D.; Tsujikawa, Kaoru; Perruzzi, Carole; Adini, Irit; Swerlick, Robert A.; Börnstein, Paul; Lawler, Jack; Benjamin, Laura E.

doi:10.1152/ajpheart.01246.2008

Cited by 48 publications

(54 citation statements)

References 39 publications

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“…This observation is consistent with increased activation of survival and proliferative pathways in endothelial cells that are isolated from TSP-1-null mice (Wang et al 2006). In addition, elevated levels of Akt phosphorylation are seen in the retinas of TSP-1-null mice (Sun et al 2009). Because Akt mediates survival of endothelial cells, the data indicate that TSP-1 inhibits angiogenesis by antagonizing survival pathways while also activating apoptotic pathways.…”

Section: Vegf Bioavailability and Activitysupporting

confidence: 76%

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Lawler

2012

Cold Spring Harbor Perspectives in Medicine

412

335

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Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration, proliferation, survival, and apoptosis and by antagonizing the activity of VEGF. Several of the membrane receptor systems and signal transduction molecules that mediate the effects of TSP-1 and TSP-2 have been elucidated. TSP-1 and TSP-2 exert their direct effects through CD36, CD47, and integrins. Recent data indicate that CD36 and b1 integrins collaborate to transmit the signals that are initiated by TSP-1 and TSP-2. Furthermore, these receptors appear to associate with VEGFR2 to form a platform for the integration of positive and negative signals for angiogenesis. Cross talk between pro-and antiangiogenic signal transduction pathways may enable TSP-1 and TSP-2 to inhibit angiogenesis by antagonizing survival pathways while also activating apoptotic pathways. CD36 and CD47 are both involved in the suppression of nitric oxide (NO). Advances in understanding of the molecular regulation of angiogenesis by TSP have paved the way for innovations in experimental treatment of cancers and will likely continue to offer vast avenues for discovery in other disease processes as well.

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Section: Vegf Bioavailability and Activitysupporting

confidence: 76%

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Lawler

2012

Cold Spring Harbor Perspectives in Medicine

412

335

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“…Ligation of CD47 by physiological concentrations of TSP1 inhibits VEGF-induced cGMP synthesis in endothelial cells (19,20) eNOS, soluble guanylate cyclase, and cGMP-dependent protein kinase are known targets of this CD47 signal (49,50). Direct inhibition of VEGFR2 activation adds a much broader control of this angiogenic pathway via CD47 and is consistent with the elevated Akt phosphorylation reported in retinas of TSP1-null mice (23). Akt phosphorylation is inhibited by engagement of CD47, which, in addition to controlling activation of eNOS, controls a broad range of prosurvival signaling in endothelial cells (2,51).…”

Section: Discussionsupporting

confidence: 61%

“…Although TSP1 has been recognized as an endogenous angiogenesis inhibitor for 20 years, the receptors and molecular mechanisms that mediate this activity remain controversial (11,23,43). Our data reveal a new mechanism by which TSP1 FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

“…Ligation of CD36 modulates VEGF signaling, and CD36 was recently found to co-immunoprecipitate in a complex with ␤1 integrins and VEGFR2 (16). TSP1 limits microvascular survival in retinal hyperoxia, which correlates with CD36 association with Src versus Fyn and antagonism of Akt survival signaling (23). ␤1 integrins were also implicated in the antiangiogenic activity of TSP1 in conjunction with CD36 (47).…”

Section: Discussionmentioning

confidence: 99%

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Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

Kaur

Martin‐Manso

Pendrak

et al. 2010

Journal of Biological Chemistry

205

222

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Thrombospondin-1 (TSP1) can inhibit angiogenic responses directly by interacting with VEGF and indirectly by engaging several endothelial cell TSP1 receptors. We now describe a more potent mechanism by which TSP1 inhibits VEGF receptor-2 (VEGFR2) activation through engaging its receptor CD47. CD47 ligation is known to inhibit downstream signaling targets of VEGFR2, including endothelial nitric-oxide synthase and soluble guanylate cyclase, but direct effects on VEGFR2 have not been examined. Based on FRET and co-immunoprecipitation, CD47 constitutively associated with VEGFR2. Ligation of CD47 by TSP1 abolished resonance energy transfer with VEGFR2 and inhibited phosphorylation of VEGFR2 and its downstream target Akt without inhibiting VEGF binding to VEGFR2. The inhibitory activity of TSP1 in large vessel and microvascular endothelial cells was replicated by a recombinant domain of the protein containing its CD47-binding site and by a CD47-binding peptide derived from this domain but not by the CD36-binding domain of TSP1. Inhibition of VEGFR2 phosphorylation was lost when CD47 expression was suppressed in human endothelial cells and in murine CD47-null cells. These results reveal that anti-angiogenic signaling through CD47 is highly redundant and extends beyond inhibition of nitric oxide signaling to global inhibition of VEGFR2 signaling.

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“…Studies in humans have suggested the importance of CD36 function in both lipid uptake and inflammatory processes (9). Increased CD36 expression on monocytes has been linked to monocyte activation in the diabetic state (10,11), and the levels of a circulating CD36 form in plasma have been related to insulin resistance and atherosclerotic plaque instability (12,13). Common CD36 genetic polymorphisms have been associated with risk of the metabolic syndrome (14), diabetes-linked coronary disease (15), and stroke (16) with variants that reduced CD36 protein expression associating with a protective atherogenic lipid profile (17).…”

mentioning

confidence: 99%

CD36 Protein Is Involved in Store-operated Calcium Flux, Phospholipase A2 Activation, and Production of Prostaglandin E2

Kuda¹,

Jenkins

Skinner³

et al. 2011

Journal of Biological Chemistry

107

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The scavenger receptor FAT/CD36 contributes to the inflammation associated with diabetes, atherosclerosis, thrombosis, and Alzheimer disease. Underlying mechanisms include CD36 promotion of oxidative stress and its signaling to stress kinases. Here we document an additional mechanism for the role of CD36 in inflammation. CD36 regulates membrane calcium influx in response to endoplasmic reticulum (ER) stress, release of arachidonic acid (AA) from cellular membranes by cytoplasmic phospholipase A 2 ␣ (cPLA 2 ␣) and contributes to the generation of proinflammatory eicosanoids. CHO cells stably expressing human CD36 released severalfold more AA and prostaglandin E 2 (PGE 2 ), a major product of AA metabolism by cyclooxygenases, in response to thapsigargin-induced ER stress as compared with control cells. Calcium influx after ER calcium release resulted in phosphorylation of cPLA 2 and its translocation to membranes in a CD36-dependent manner. Peritoneal macrophages from CD36 ؊/؊ mice exhibited diminished calcium transients and reduced AA release after thapsigargin or UTP treatment with decreased ERK1/2 and cPLA 2 phosphorylation. However, PGE 2 production was unexpectedly enhanced in CD36 ؊/؊ macrophages, which probably resulted from a large induction of cyclooxygenase 2 mRNA and protein. The data demonstrate participation of CD36 in membrane calcium influx in response to ER stress or purinergic receptor stimulation resulting in AA liberation for PGE 2 formation. Collectively, these results identify a mechanism contributing to the pleiotropic proinflammatory effects of CD36 and suggest that its targeted inhibition may reduce the acute inflammatory response.

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Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina

Abstract: modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina.

Cited by 48 publications

References 39 publications

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Thrombospondin-1 Inhibits VEGF Receptor-2 Signaling by Disrupting Its Association with CD47

CD36 Protein Is Involved in Store-operated Calcium Flux, Phospholipase A2 Activation, and Production of Prostaglandin E2

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