Role of Transient Receptor Potential Ankyrin‐1 (TRPA1) in Endothelial‐Specific Effects of Diverse Aldehydes

Abstract

IntroductionStructurally diverse aldehydes are found in abundance in the environment including in foods, beverages and tobacco‐derived aerosols. Some aldehydes are associated with cardiovascular disease risk especially in cigarettes smokers, however, the detailed mechanisms by which aldehydes influence cardiovascular health and disease are incompletely known.ObjectiveBecause reactive aldehydes, in general, are considered instigators of endothelium dysfunction, we explored the direct effects of a diverse set of aldehydes in isolated murine blood vessels, i.e., aorta and superior mesenteric artery (SMA).MethodsAldehydes: acetaldehyde (AA); formaldehyde (FA); cinnamaldehyde (CA); crotonaldehyde (CR); and a TRPA1 agonist, allyl isothiocyanate (AITC, mustard oil), were tested for vascular effects in isolated murine aorta and SMA using isometric myography.ResultsAll aldehydes induced endothelium‐dependent relaxation in SMA. AA (1–100 mM), FA (30–1,500 μM), CA (30–300 μM) and CR (1–100 μM) strongly and reversibly relaxed (>75% relaxation) agonist‐induced contractions. High levels of FA (1.2–1.6 mM) and CR (>300 μM) irreversibly altered vascular function in aorta and SMA. To identify the mechanism of aldehyde‐induced relaxations, isolated blood vessels were pre‐contracted with phenylephrine (PE), U46,619 (thromboxane A2 analog), or 60 mM K+ (High K) and then exposed to AA, FA, CA, CR or AITC with intact or mechanically‐impaired endothelium (air‐perfused) as well as in the absence or presence of: 1) Nω‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME); 2) an inhibitor of guanylyl cyclase (ODQ); and, 3) a TRPA1 antagonist (A967079; 1 μM). The sensitivity (EC50) but not the efficacy (% decreased tension) of FA‐ and AA‐induced relaxations was dependent on the contractile agonist (i.e., PE < U46,619 ≤ High K) indicating multiple mechanisms. In PE pre‐contracted SMA, vasorelaxations at the lowest levels of AA, FA, CA, CR and AITC were inhibited significantly by mechanically‐disrupted endothelium, L‐NAME, ODQ, and by TRPA1 antagonist except for AA, which was TRPA1 independent. TRPA1 was co‐localized with isolectin immunofluorescent staining in SMA endothelium but not in aorta.ConclusionBecause low levels (physiological) of several aldehydes (FA, CA, CR) induce reversible and efficacious vasorelaxations via TRPA1 channels, we propose that endogenous and exogenous sources of these aldehydes may significantly impact gut (mesenteric) blood flow to augment postprandial hyperemia in aid of digestion and nutrient uptake.Support or Funding InformationResearch funding from the National Institutes of Health: GM127607, HL122676, U54HL120163.