Histamine induces intracellular Ca2+ oscillations and nitric oxide release in endothelial cells from brain microvascular circulation. Issue 2 (16th July 2019)

• Record Type: Journal Article
• Authors: Berra‐Romani, Roberto; Faris, Pawan; Pellavio, Giorgia; Orgiu, Matteo; Negri, Sharon; Forcaia, Greta; Var‐‐‐gaz‐Guadarrama, Verónica; Garcia‐Carrasco, Mario; Botta, Laura; Sancini, Giulio; Laforenza, Umberto; Moccia, Francesco
• Is Part Of: Journal of cellular physiology. Volume 235:Issue 2(2020:Feb.)
• Page Start: 1515
• Page End: 1530
• Publication Date: 2019-07-16
• Subjects: Ca2+ oscillations -- cerebral blood flow -- H1 receptor -- histamine -- nitric oxide; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.29071
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: The neuromodulator histamine is able to vasorelax in human cerebral, meningeal and temporal arteries via endothelial histamine 1 receptors (H1 Rs) which result in the downstream production of nitric oxide (NO), the most powerful vasodilator transmitter in the brain. Although endothelial Ca 2+ signals drive histamine‐induced NO release throughout the peripheral circulation, the mechanism by which histamine evokes NO production in human cerebrovascular endothelial cells is still unknown. Herein, we exploited the human cerebral microvascular endothelial cell line, hCMEC/D3, to assess the role of intracellular Ca 2+ signaling in histamine‐induced NO release. To achieve this goal, hCMEC/D3 cells were loaded with the Ca 2+ ‐ and NO‐sensitive dyes, Fura‐2/AM and DAF‐FM/AM, respectively. Histamine elicited repetitive oscillations in intracellular Ca 2+ concentration in hCMEC/D3 cells throughout a concentration range spanning from 1 pM up to 300 μM. The oscillatory Ca 2+ response was suppressed by the inhibition of H 1 Rs with pyrilamine, whereas H 1 R was abundantly expressed at the protein level. We further found that histamine‐induced intracellular Ca 2+ oscillations were initiated by endogenous Ca 2+ mobilization through inositol‐1, 4, 5‐trisphosphate‐ and nicotinic acid dinucleotide phosphate‐sensitive channels and maintained over time by store‐operated Ca 2+ entry. In addition, histamine evoked robust NO release that was prevented by interfering with the accompanying intracellular Ca 2+ oscillations, thereby confirming that the endothelial NO synthase is recruited by Ca 2+ spikes also in hCMEC/D3 cells. These data provide the first evidence that histamine evokes NO production from human cerebrovascular endothelial cells through intracellular Ca 2+ oscillations, thereby shedding novel light on the mechanisms by which this neuromodulator controls cerebral blood flow. Abstract : Histamine induces vasodilatation in human cranial arteries by inducing endothelial‐dependent NO release via H1 receptors (H1 Rs). Herein, we found that H 1 R activation results in intracellular Ca 2+ oscillations in a human brain microvascular endothelial cell line. We further show that the intracellular Ca 2+ oscillations drive NO release.