ABSTRACT
Formaldehyde (FA), the smallest aldehyde, is generated endogenously, and is widespread in the environment in foods, beverages and as a gas phase product of incomplete combustion. The main metabolite of FA, formate, was increased significantly in murine urine (â¼3×) after overnight feeding. Because feeding increases mesenteric blood flow, we explored the direct effects of FA in isolated murine superior mesenteric artery (SMA). Over the concentration range of 30-1,200 µM, FA strongly and reversibly relaxed contractions of SMA induced by three different agonists: phenylephrine (PE), thromboxane A2 analog (U46,619) and high potassium (60K, 60 mM K+). Formate (to 1.5 mM) induced a modest relaxation. FA (>1,500 µM) irreversibly depressed vascular function in SMA indicating vasotoxicity. The sensitivity (EC50) but not the efficacy (% relaxation) of FA-induced relaxations was dependent on blood vessel type (SMA << aorta) and contractile agonist (PE, EC50= 52 ± 14 µM; U46,619, EC50= 514 ± 129 µM; 60K, EC50= 1,093 ± 87 µM). The most sensitive component of FA vasorelaxation was within physiological levels (30-150 µM) and was inhibited significantly by: (1) mechanically impaired endothelium; (2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); (3) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); (4) guanylyl cyclase (GC) inhibitor (ODQ); and, (5) K+ channel inhibitor (BaCl2). A similar mechanism of SMA vasorelaxation was stimulated by the TRPA1 agonist cinnamaldehyde. Positive TRPA1 immunofluorescent staining and gene-specific sequence were present in SMA but not in aorta. These data indicate FA, but not formate, robustly relaxes SMA via a sensitive TRPA1- and endothelium-dependent mechanism that is absent in aorta. Thus, as FA levels increase with feeding, FA likely contributes to the physiological reflex of post-prandial hyperemia via SMA vasodilatation.
ABSTRACT
Calcium (Ca2+) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca2+ concentration ([Ca2+]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca2+-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca2+]i. In this review, we discuss the major Ca2+-permeable channels expressed in VSM and their contribution to vascular physiology and pathology.