Blockade of Thrombospondin-1-CD47 Interactions Prevents Necrosis of Full Thickness Skin Grafts

Isenberg, Jeff S.; Pappan, Loretta K.; Romeo, Martin J.; Abu‐Asab, Mones; Tsokos, Maria; Wink, David A.; Frazier, William A.; Roberts, D. A.

doi:10.1097/sla.0b013e31815685dc

Cited by 80 publications

(80 citation statements)

References 56 publications

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“…Vascular cells and platelets lacking TSP1 demonstrate significant differences in both basal and NO-stimulated cGMP levels compared with cells that produce functional TSP1 (2,3,43). In contrast vascular cells obtained from TSP2-null animals do not demonstrate differences in cGMP accumulation under either basal or NOstimulated conditions.…”

Section: Discussionmentioning

confidence: 82%

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Differential Interactions of Thrombospondin-1, -2, and -4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses

Isenberg

Annis

Pendrak

et al. 2009

Journal of Biological Chemistry

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134

163

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Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47. Because CD47 binding motifs are conserved in the C-terminal signature domains of all five thrombospondins and indirect evidence has implied CD47 interactions with other family members, we compared activities of recombinant signature domains of thrombospondin-1, -2, and -4 to interact with CD47 and modulate cGMP signaling. Signature domains of thrombospondin-2 and -4 were less active than that of thrombospondin-1 for inhibiting binding of radiolabeled signature domain of thrombospondin-1 or SIRP␣ (signal-regulatory protein) to cells expressing CD47. Consistent with this binding selectivity, the signature domain of thrombospondin-1 was more potent than those of thrombospondin-2 or -4 for inhibiting NO-stimulated cGMP synthesis in vascular smooth muscle cells and downstream effects on cell adhesion. In contrast to thrombospondin-1-and CD47-null cells, primary vascular cells from thrombospondin-2-null mice lack enhanced basal and NO-stimulated cGMP signaling. Effects of endogenous thrombospondin-2 on NO/cGMP signaling could be detected only in thrombospondin-1-null cells. Furthermore, tissue survival of ischemic injury and acute recovery of blood flow in thrombospondin-2-nulls resembles that of wild type mice. Therefore, thrombospondin-1 is the dominant regulator of NO/cGMP signaling via CD47, and its limiting role in acute ischemic injury responses is not shared by thrombospondin-2.Nitric oxide (NO) is a major mediator of intracellular and paracellular signal transduction. NO preserves vascular health by minimizing the adhesion of inflammatory cells to the vessel wall, limiting platelet activation, and increasing blood vessel diameter and blood flow by relaxing vascular smooth muscle cells (VSMC).3 These actions of NO are mediated by activating soluble isoforms of guanylate cyclase (sGC) to increase cGMP levels, resulting in downstream activation of cGMP-dependent protein kinases and ion channels (1).Physiological NO/cGMP signaling is limited by several phosphodiesterases that degrade cGMP and by thrombospondin-1 (TSP). TSP1 is a secreted protein that is produced by vascular and inflammatory cells that regulates cellular behavior by engaging several cell surface receptors. Recently we reported that TSP1 potently blocks NO-stimulated prosurvival responses in endothelial and VSMC (2, 3). TSP1 also plays a role in promoting platelet thrombus formation and hemostasis by antagonizing the antithrombotic activity of NO (4). In all of these vascular cells, picomolar concentrations of TSP1 are sufficient to block NO-stimulated fluxes in cGMP by engaging its receptor CD47 (5). Nanomolar concentrations of TSP1 further inhibit the same signaling pathway by inhibiting CD36-mediated uptake of myristate into vascular cells (6). In vivo, mice lacking TSP1 demonstrate elevated basal tissue cGMP levels and greater increases in regional blood flow in response to a NO challenge than wild type controls (4). After an ischemic insult, the absence of TSP1 o...

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Section: Discussionmentioning

confidence: 82%

“…Consequently, TSP1-null animals demonstrate enhanced tissue perfusion and survival to various ischemic challenges compared with wild type animals due to enhanced NO/cGMP responses (4,38,43). In contrast, TSP2-null animals showed no tissue survival or perfusion advantage in the same ischemia models.…”

Section: Discussionmentioning

confidence: 93%

Differential Interactions of Thrombospondin-1, -2, and -4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses

Isenberg

Annis

Pendrak

et al. 2009

Journal of Biological Chemistry

Self Cite

134

163

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show abstract

“…TSP-1-null and CD47-null mice display decreased necrosis and significantly improved healing in the cutaneous flap model and full-thickness skin grafts. Whereas grafts performed onto wild-type mice fail, the majority of those performed with TSP-1-null or CD47-null mice survive (Isenberg et al 2008). Thus, targeting the TSP-1/CD47/NO signaling axis may promote healing of skin grafts.…”

Section: Therapeutic Opportunities For Regulation Of Angiogenesis Witmentioning

confidence: 99%

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

Lawler

2012

Cold Spring Harbor Perspectives in Medicine

416

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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“…At nanomolar TSP1 concentrations, this inhibition can be mediated by CD36 (14), but at physiological circulating plasma TSP1 concentrations (100 -200 pM), CD47 is the necessary TSP1 receptor for inhibiting activation of soluble guanylate cyclase (20) or cGMP-dependent protein kinase (21). CD47-null and TSP1-null mice show similarly enhanced survival of full thickness skin grafts and increased angiogenic responses in the wound bed (22).…”

mentioning

confidence: 99%

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

Kaur

Martin‐Manso

Pendrak

et al. 2010

Journal of Biological Chemistry

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207

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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Blockade of Thrombospondin-1-CD47 Interactions Prevents Necrosis of Full Thickness Skin Grafts

Cited by 80 publications

References 56 publications

Differential Interactions of Thrombospondin-1, -2, and -4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses

Differential Interactions of Thrombospondin-1, -2, and -4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses

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

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