1 Zinc in the cytoplasm of perivascular sensory nerves activates transient receptor potential ankyrin 1 (TRPA1) that causes calcium influx and, in turn, releases calcitonin gene-related peptide (CGRP). CGRP binds to its G-protein coupled receptor (CLR-RAMP1-RCP) on the smooth muscle to cause cAMP-dependent hyperpolarization and relaxation. 2 Vascular smooth muscle cells are relaxed by cytoplasmic zinc that inhibits voltage-gated calcium channels (VGCC). 3 In the endothelium, increased cytoplasmic zinc using pyrithione and clioquinol causes relaxation of the smooth muscle by increasing dilatory prostanoid signaling. Nitric oxide synthase (NOS) function requires zinc, but its activity is not stimulated by excess zinc, rather it is inhibited by zinc deprivation. Image partly created with BioRender.com.