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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1524-1532.
Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-08-041970.
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Submitted August 16, 2006
Accepted September 19, 2006
Deletion of tetraspanin CD151 results in decreased pathological angiogenesis in vivo and in vitro
Yoshito Takeda, Alexander R Kazarov, Catherine E Butterfield, Benjamin D Hopkins, Laura E Benjamin, Arja Kaipainen, and Martin E Hemler*
Dana-Farber Cancer Institute, Boston, MA
Vascular Biology Program, Children's Hospital, Boston, MA
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
* Corresponding author; email: martin_hemler{at}dfci.harvard.edu.
Tetraspanin protein CD151 is abundant on endothelial cells. To determine whether CD151 affects angiogenesis, CD151-null mice were prepared. CD151-null mice showed no vascular defects during normal development, or during neonatal oxygen-induced retinopathy. However, CD151-null mice showed impaired pathological angiogenesis in other in vivo assays (Matrigel plug, corneal micropocket, tumor implantation) and in the ex vivo aortic ring assay. CD151-null mouse lung endothelial cells (MLECs) showed normal adhesion and proliferation, but marked alterations in vitro, in assays relevant to angiogenesis (migration, spreading, invasion, Matrigel contraction, tube and cable formation, spheroid sprouting). Consistent with these functional impairments, and with the close, preferential association of CD151 with laminin-binding integrins, CD151-null MLECs also showed selective signaling defects, particularly on laminin substrate. Adhesion-dependent activation of PKB/c-Akt, e-NOS, Rac and Cdc42 was diminished, but Raf, ERK, p38 MAP kinase, FAK and Src were unaltered. In CD151-null MLECs, connections were disrupted between laminin-binding integrins and at least five other proteins. In conclusion, CD151 modulates molecular organization of laminin-binding integrins, thereby supporting secondary (i.e. post-cell adhesion) functions of endothelial cells, which are needed for some types of pathological angiogenesis in vivo. Selective effects of CD151 on pathological angiogenesis make it a potentially useful target for anti-cancer therapy.
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