| First Author | Collier DM | Year | 2019 |
| Journal | Am J Physiol Heart Circ Physiol | PubMed ID | 30848676 |
| Mgi Jnum | J:272385 | Mgi Id | MGI:6284673 |
| Doi | 10.1152/ajpheart.00655.2018 | Citation | Collier DM, et al. (2019) Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation. Am J Physiol Heart Circ Physiol |
| abstractText | Histone proteins are elevated in the circulation after traumatic injury owing to cellular lysis and release from neutrophils. Elevated circulating histones in trauma contribute to coagulopathy and mortality through a mechanism suspected to involve endothelial cell (EC) dysfunction. However, the functional consequences of histone exposure on intact blood vessels are unknown. Here, we sought to understand the effects of clinically relevant concentrations of histones on the endothelium in intact, resistance-sized, mesenteric arteries (MAs). EC Ca(2+) was measured with high spatial and temporal resolution in MAs from mice selectively expressing the EC-specific, genetically encoded ratiometric Ca(2+) indicator, Cx40-GCaMP-GR, and vessel diameter was measured by edge detection. Application of purified histone protein directly to the endothelium of en face mouse and human MA preparations produced large Ca(2+) signals that spread within and between ECs. Surprisingly, luminal application of histones had no effect on the diameter of pressurized arteries. Instead, after prolonged exposure (30 minutes), it reduced dilations to endothelium-dependent vasodilators and ultimately caused death of ~25% of ECs, as evidenced by markedly elevated cytosolic Ca(2+) levels (793 +/- 75 nM) and uptake of propidium iodide. Removal of extracellular Ca(2+), but not depletion of intracellular Ca(2+) stores, prevented histone-induced Ca(2+) signals. Histone-induced signals were not suppressed by TRPV4 channel inhibition (100 nM GSK2193874) or genetic ablation of TRPV4 channels or TLR4 receptors. These data demonstrate that histones are robust activators of non-canonical EC Ca(2+) signaling that cause vascular dysfunction through loss of endothelium-dependent dilation in resistance-sized MAs. |
