Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle

Nat Commun. 2021 Jun 1;12(1):3296. doi: 10.1038/s41467-021-23198-6.


Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcium Channels, N-Type / metabolism
  • Chelating Agents / pharmacology
  • Cytoplasm / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / innervation
  • Endothelium, Vascular / metabolism*
  • Ethylenediamines / pharmacology
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology*
  • Patch-Clamp Techniques
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Prostaglandins / metabolism
  • Rats
  • Sensory Receptor Cells / metabolism*
  • TRPA1 Cation Channel / genetics
  • TRPA1 Cation Channel / metabolism
  • Vasodilation / drug effects
  • Vasodilation / physiology*
  • Zinc / metabolism*


  • Calcium Channels, N-Type
  • Chelating Agents
  • Ethylenediamines
  • Prostaglandins
  • TRPA1 Cation Channel
  • Prostaglandin-Endoperoxide Synthases
  • Zinc
  • Calcitonin Gene-Related Peptide
  • N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine