Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries

Abstract

Inadequate perfusion of solid cancer tissue results in low local nutrient and oxygen levels and accumulation of acidic waste products. Previous investigations have focused primarily on tumor blood vessel architecture, and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistance-sized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared with normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO synthase expression are increased in colon cancer feed arteries compared with normal colon arteries, whereas vasorelaxation to exogenous NO donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO synthase inhibition. Rhythmic oscillations in vascular tone, known as vasomotion, are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. NEW & NOTEWORTHY Local vascular resistance influences tumor perfusion. Arteries supplying human colonic adenocarcinomas show enhanced vasorelaxation and reduced vasocontraction mainly due to elevated nitric oxide-mediated signaling. Rhythmic oscillations in tone, known as vasomotion, are attenuated in colon cancer feed arteries.

PTPRG is an ischemia risk locus essential for HCO3–-dependent regulation of endothelial function and tissue perfusion

“…We determined protein expression levels of eNOS in basilar and mesenteric arteries by immunoblotting using previously described antibodies ( Boedtkjer et al, 2011 ; Voss et al, 2019 ). Arteries were snap frozen in liquid nitrogen and then homogenized using pellet pestles (Sigma-Aldrich, Denmark) in a lysis buffer at pH 7.5 containing (in mM) 20 Tris-HCl, 150 NaCl, 5 ethylene glycol tetraacetic acid (EGTA), 10 NaF, 20 β-glycerophosphate sodium salt, and HALT protease and phosphatase inhibitor cocktail (Thermo Scientific, Denmark).…”

“…We determined protein expression levels of eNOS in basilar and mesenteric arteries by immunoblotting using previously described antibodies (28,49). Arteries were snap frozen in liquid nitrogen and then homogenized using pellet pestles (Sigma-Aldrich, Denmark) in a lysis buffer at values were calculated for a region of interest (100×100 pixels) in the second posterior bifurcation of the middle cerebral artery corresponding to the somatosensory barrel cortex contralateral to the whisker stimulation (50).…”

Upregulated Na+/H+-Exchange Protects Human Colon Cancer Tissue against Intracellular Acidification

“…We sampled biopsies from human colon resections immediately after excision from patients undergoing colon cancer surgery at Regional Hospital Randers, Denmark [7]. Normal colon tissue was biopsied from the same surgical specimens at a minimal distance of 10 cm from the macroscopic tumor border.…”

The Acidic Tumor Microenvironment as a Driver of Cancer

“…The formation of new blood vessels (i.e., angiogenesis) and incorporation of existing blood vessels from surrounding tissue (i.e., co-option) partially counteract the diffusion limitations (120). As discussed in greater detail below, the tumor blood vessels may also undergo functional adaptations that promote blood flow delivery to the cancer tissue (121,122). In fact, blood flow delivery to some tumor regions can be substantially higher than to corresponding normal tissue (123), although O 2 delivery usually remains insufficient to match the elevated metabolic demand.…”

“…As a consequence, extratumoral blood vessels contribute substantially to tumor vascular resistance, and changes in the contractile state of tumor feed arteries are expected to significantly modify tumor blood flow. Murine breast cancer feed arteries and human colon cancer feed arteries show functional specialization that facilitates vasodilation or inhibits vasocontraction (121,122) and thereby minimizes vascular resistance compared to corresponding normal arteries. The mechanisms explaining the reduced vascular resistance of cancer feed arteries depend on the source of the arteries.…”