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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2669-2670.
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INSIDE BLOOD
Comment on Caselli et al, page 2718
Totally tubular: virally induced endothelial tube formation
Philip E. Pellett
CLEVELAND CLINIC
Using primary human vascular endothelial cells grown on a surface coated with a basement membrane extract, Caselli and coworkers found that infection with human herpesvirus 8 (HHV-8, or Kaposi sarcoma–associated herpesvirus) induces the formation of capillary-like tubules that are a hallmark of angiogenesis.
The tubule induction was dependent on monocyte chemoattractant protein 1 (MCP-1), an inflammatory cytokine with angiogenic properties.1,2 MCP-1 induction appeared to be the end point of a tightly channeled, virus-induced NF- B response (Figure 1). Interest in this observation is heightened because HHV-8 is the etiologic agent of Kaposi sarcoma (KS), a neoplasm that occurs in immune-compromised individuals, elderly men from the Mediterranean region, and in children and adults in some parts of equatorial Africa. KS lesions are defined by a profusion of capillary-like slits that are lined with HHV-8–infected endothelial cells. HHV-8 encodes at least 2 proteins with demonstrated angiogenic properties when studied outside the context of viral infection: a G protein–coupled receptor (vGPCR) that is related to CXCR2,3,4 and a homolog of interleukin 6. Among other things, vGPCR induces NF-B and MCP-1.5 The paper by Caselli et al is important, in part, because the angiogenic effect occurred in the context of productive viral infection. It will be interesting to see whether the dots can be connected between these experimental biologic systems, and ultimately to pathogenesis in humans.
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Human umbilical vein endothelial cells (HUVECs) are induced to form capillary-like tubules in response to HHV-8 infection, a process that is dependent on NF-B–induced MCP-1. Professional illustration by Marie Dauenheimer.
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Primary vascular endothelial cells are able to spontaneously form capillary-like tubules, and indeed such tubules formed in the system used by Caselli and coworkers. Not only did HHV-8 infection accelerate this process, but an antibody against MCP-1 inhibited virus-induced tubule formation; the same antibody had no inhibitory effect against the spontaneous process. Thus, angiogenesis is a complex process that has multiple triggers. Because the MCP-1 antibody blocks HHV-8–induced tubule formation but has no substantial effect on spontaneous tube formation, this novel pathway is a potential target for novel KS therapeutics.
NF-B is a central regulator of a variety of cellular genes that control inflammatory and immune responses, as well as cell proliferation and survival. Although many genes are potentially responsive to NF-B, only a subset of its target genes is induced under a given set of activating conditions. The requirement of NF-B for MCP-1 induction in HHV-8–infected cells, in the absence of a broad anti-inflammatory response, emphasizes the specificity with which NF-B responses can be channeled.
Several items remain for future study. The role of NF-B needs to be fleshed out, and the other pathways that regulate MCP-1 expression need to be identified. The MCP-1–dependent and –independent pathways for endothelial cell tubule formation need to be defined and their point of convergence identified. Coupling this system with virus genetics will strengthen understanding of the angiogenic mechanism and help dissect the complex process of KS tumor formation: what are the viral factors and how do they work?
Footnotes
The author declares no competing financial interests. 
REFERENCES
- Yamada M, Kim S, Egashira K, et al. Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2003; 23:1996–2001.[Abstract/Free Full Text]
- Salcedo R, Ponce ML, Young HA, et al. Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 2000; 96:34–40.[Abstract/Free Full Text]
- Shan B, Morris CA, Zhuo Y, et al. Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol Prepublished on December 26, 2006, as DOI 10.1016/j.yjmcc.2006.08.004.
- Bais C, Santomasso B, Coso O, et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998; 391:86–89.[CrossRef][Medline]
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- Schwarz M and Murphy PM. Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-kappa B and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol 2001; 167:505–513.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1–dependent capillary-like structure formation: role of the IKK/NF-B pathway
- Elisabetta Caselli, Simona Fiorentini, Carla Amici, Dario Di Luca, Arnaldo Caruso, and M. Gabriella Santoro
Blood 2007 109: 2718-2726.
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