Abstract
Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40−/−), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40−/− but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40−/− mice. As a result, Cx40−/− mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment.
Highlights
Angiogenesis, i.e. the growth of new capillaries sprouting from pre-existing blood vessels, is fundamental to many physiological and pathological events, including tumor survival and growth [1]
Using wild type (WT), Cx40–/– and Tie2Cx40 mice, as well as a peptide known to target Cx40, we show that loss of Cx40 is associated with decreased angiogenesis in different in vitro, ex vivo and in vivo models
We further demonstrate that Cx40 participates to control the growth of melanoma and urogenital tumors in association with changes of tumoralvessels, and altered eNOS activity
Summary
Angiogenesis, i.e. the growth of new capillaries sprouting from pre-existing blood vessels, is fundamental to many physiological and pathological events, including tumor survival and growth [1]. The mechanism leading to angiogenesis requires the coordinated response of endothelial cells (ECs) to multiple stimuli [2], including basic fibroblast growth factor, vascular endothelial growth factor and nitric oxide (NO), which stimulate the proliferation, survival, migration and differentiation of ECs [3,4,5]. As yet, such molecules have shown modest and transient effects in cancer therapy [6,7,8], calling for the identification of novel endothelial targets. Cx40-null mice (Cx40–/–) display impaired endothelial-dependent dilation of blood-vessels in response to various agents [15, 16], and are hypertensive mainly due to increased renin secretion [17,18,19]
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