Abstract
Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.
Highlights
Angiogenesis, i.e., the formation of new blood vessels, is critical for providing the oxygen and nutrients which are necessary for tumor growth [1–3]
Parallel experiments revealed that supplementing the plugs with 37,43Gap27, a peptide which inhibits Cx37 channels [39–41], reduced the angiogenesis in WT mice, an effect which was not observed in plugs supplemented with a scrambled version of this peptide (Figure 1C)
We investigated whether Cx37, a major connexin (Cx) of endothelial cells (EC) [18,22,30,35,42], is involved in the control of tumor angiogenesis
Summary
Angiogenesis, i.e., the formation of new blood vessels, is critical for providing the oxygen and nutrients which are necessary for tumor growth [1–3] It requires a fine-tuned coordination between the proliferation, migration and differentiation of both endothelial (EC) and mural cells [4,5]. The overexpression of pro-angiogenic factors results in the formation of irregular and tortuous vessels, which feature a discontinuous pericyte coverage, a high permeability [1,12] and a fenestrated basement membrane [13]. These features compromise the barrier integrity of the tumor vasculature and its perfusion, resulting in a sustained hypoxia, which may contribute to tumor maintenance and resistance to chemotherapy [14,15]
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