Endothelin-1 potentiates TRPV1-mediated vasoconstriction of human
adipose arterioles in a protein kinase C-dependent manner
Abstract
Background: Vascular TRPV channels have emerged as important regulators
of vascular tone. TRPV1 and endothelin-1 (ET-1) are independently
associated with the pathophysiology of coronary vasospasm but the
relationship between their vasomotor functions remains unclear. We
characterized the vasomotor function of TRPV1 channels in human
arterioles and investigated regulation of their vasomotor function by
ET-1. Approach: Arterioles were threaded on two metal wires,
equilibrated in a physiological buffer at 37 oC and exposed to
increasing concentrations of capsaicin in the absence or presence of
SB366791 (TRPV1-selective inhibitor) or GF109203X (PKC-selective
inhibitor). Some arterioles were preconstricted with ET-1 or
phenylephrine or high K+ buffer. TRPV1 mRNA and protein expression in
human arteries were assessed. Results: TRPV1 transcripts and proteins
were detected in human resistance arteries. Capsaicin (1 µM) induced
concentration-dependent constriction of endothelium-intact (35 ± 8 %)
and endothelium-denuded (43 ± 11 %) human adipose arterioles (HAA),
which was significantly inhibited by SB366791 (0.2 ± 0.1 %).
Preconstriction of HAA with ET-1, but not high potassium buffer or
phenylephrine, significantly potentiated capsaicin-induced constriction
(33 ± 7 % vs 12 ± 8 %). GF109203X significantly inhibited potentiation
of capsaicin-induced constriction by ET-1. Conclusion: TRPV1 channels
are expressed in the human vasculature and can influence vascular tone
of human arterioles upon activation. Their vasomotor function is
modulated by ET-1, mediated in part by PKC.. These findings reveal a
novel interplay between ET-1 signaling and TRPV1 channels in human VSMC,
adding to our understanding of the ion channel mechanisms that regulate
human arteriolar tone and may also contribute to the pathophysiology of
coronary vasospasm.