Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Abstract

Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor growth. Such vascular remodeling can offer selective targets to pharmacologically modulate tumor perfusion and thereby improve the efficacy of conventional anticancer treatments. Radiotherapy and chemotherapy can, indeed, take advantage of a better tumor oxygenation and drug delivery, respectively, both partly dependent on the tumor blood supply.Here, we showed that isolated tumor arterioles mounted in a pressure myograph have the ability, contrary to size-matched healthy arterioles, to contract in response to a transluminal pressure increase. This myogenic tone was exquisitely dependent on the endothelin-1 pathway because it was completely abolished by the selective endothelin receptor A (ET A ) antagonist BQ123. This selectivity was additionally supported by the large increase in endothelin-1 abundance in tumors and the higher density of the ET A receptors in tumor vessels. We also documented by using laser Doppler microprobes and imaging that administration of the ET A antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered. Finally, we provided evidence that acute administration of the ET A antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy.Thus, blocking the tumor-selective increase in the vascular endothelin-1/ ET A pathway led us to unravel an important reserve of vasorelaxation that can be exploited to selectively increase tumor response to radiotherapy.

Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis

“…In addition, our data are consistent with results showing an increase in eNOS activation and leakiness of vessels in mice lacking Cav-1 and caveolae (30), because endothelial-specific expression of Cav-1 reduces eNOS activation, NO-dependent vascular function, and VEGF-stimulated permeability. However, our data differ from studies in Cav-1(Ϫ/Ϫ) mice that show decreased ischemia-induced angiogenesis (35), whereas in the present study, both VEGF-and ischemia-mediated angiogenesis are reduced by EC overexpression of Cav-1. The mechanism of impaired arteriogenesis͞angiogenesis in Cav-1(Ϫ/Ϫ) mice appears also to be due to defective VEGFR signaling to ERK, Akt, and eNOS.…”

Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism

“…It is interesting to speculate that these responses may be partially mediated by eNOS s1179 phosphorylation. ERK1͞2 is also downstream of another angiogenic factor VEGF in mediating eNOS activation (26). Of note, our observation that netrin-1 activation of ERK1͞2 is growth stimulating is consistent with the only other earlier notion regarding ERK1͞2 and netrin-1 that DCC-dependent activation of ERK1͞2 mediates netrin-1 induced axonal outgrowth (5).…”

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

“…In most human tumours investigated so far, both ET receptor subtypes have been identified (Nelson et al, 2003), although pharmacological manipulation of the endothelin axis for cancer therapy has concentrated on the potential for ET A antagonists (Nelson, 2001;Nelson et al, 2003;Sonveaux et al, 2004). Our studies suggest that the ET B agonist, IRL 1620, would be useful for short-term blood flow reduction in tumours expressing the ET B receptor and, due to its constrictive effect, IRL 1620 may also have antiangiogenic properties.…”

“…However, very few studies have investigated these factors directly. The endothelin receptor family represents a group of receptors, which has a profound role in the control of normal tissue blood flow under both physiological and pathological conditions (Haynes and Webb, 1994;Russell et al, 1998;Stjernquist, 1998) and which may be possible to exploit for selective modification of tumour blood flow , 1997, Rai and Gulati, 2003Sonveaux et al, 2004). The development of highly specific agonists and antagonists for ET-1 receptors has provided tools for studying the role of ET-1 in tumour vasculature.…”