Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Mar;190(3):535-542.
doi: 10.1016/j.ajpath.2019.11.004. Epub 2019 Dec 19.

Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

Prarthana J Dalal  1 , William A Muller  1 , David P Sullivan  2
Affiliations
Review

Endothelial Cell Calcium Signaling during Barrier Function and Inflammation

Prarthana J Dalal et al. Am J Pathol. 2020 Mar.

Abstract

Calcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiologic processes, including cell migration, angiogenesis, barrier function, and inflammation. An increase in intracellular Ca2+ concentration can trigger a number of diverse signaling pathways under both physiologic and pathologic conditions. In this review, we discuss how calcium signaling pathways in endothelial cells play an essential role in affecting barrier function and facilitating inflammation. Inflammatory mediators, such as thrombin and histamine, increase intracellular calcium levels. This calcium influx causes adherens junction disassembly and cytoskeletal rearrangements to facilitate endothelial cell retraction and increased permeability. During inflammation endothelial cell calcium entry and the calcium-related signaling events also help facilitate several leukocyte-endothelial cell interactions, such as leukocyte rolling, adhesion, and ultimately transendothelial migration.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A: Low intracellular calcium concentrations at rest are maintained by plasma membrane calcium ATPase (PMCA) and sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) channels. PMCA channels are present on the plasma membrane (PM), and SERCA channels are present on the ER membrane. Both actively transport calcium ions out of the cytoplasm and into the extracellular space and ER, respectively, to maintain low intracellular calcium concentrations. B: On stimulation of G-protein–coupled receptors (GPCRs), phospholipase C (PLC) is activated, resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 in turn induces calcium influx from the ER and extracellular space. Calcium entry from the extracellular space can occur from store-operated cation channels (SOCs) or receptor-operated cation channels (ROCs). C: During inflammation, the calcium influx into endothelial cells can facilitate dephosphorylation of nuclear factor of activated T-cells (NFAT) from phospho-NFAT (pNFAT) to NFAT. NFAT then travels to the nucleus, where it can increase transcription of ICAM1 and VCAM1.
Figure 2
Figure 2
A: Endothelial calcium and barrier function. Thrombin binds a G-protein–coupled receptor (GPCR), PAR-1, resulting in an intracellular increase in Ca2+. This activates CaMKIIδ, myosin light chain kinase (MLCK), and annexin A2. Together these molecules facilitate vascular endothelia (VE)–cadherin disassembly and actomyosin contraction, leading to increased permeability. B: Endothelial calcium and inflammation. Endothelial calcium is a key regulator for many steps of the extravasation cascade. During fast rolling, endothelial E-selectin engagement mediates an increase in intracellular calcium concentration. As leukocytes adhere, they use lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) to interact with endothelial surface intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Both of these interactions promote increased intracellular calcium. Then during transendothelial migration, homophilic platelet endothelial cell adhesion molecule (PECAM)–PECAM interactions stimulate transient receptor potential channel 6 (TRPC6), resulting in a calcium influx necessary to support diapedesis. Finally, calcium ions are required to activate myosin light chain, which facilitates cytoskeletal rearrangements during the pore closure step. PSGL1, P-selectin glycoprotein ligand 1.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Clapham D.E. Calcium signaling. Cell. 2007;131:1047–1058. - PubMed
    1. Tiruppathi C., Minshall R.D., Paria B.C., Vogel S.M., Malik A.B. Role of Ca2+ signaling in the regulation of endothelial permeability. Vascul Pharmacol. 2002;39:173–185. - PubMed
    1. Berridge M.J., Bootman M.D., Roderick H.L. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–529. - PubMed
    1. Tran Q.K., Ohashi K., Watanabe H. Calcium signalling in endothelial cells. Cardiovasc Res. 2000;48:13–22. - PubMed
    1. Tiruppathi C., Ahmmed G.U., Vogel S.M., Malik A.B. Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation. 2006;13:693–708. - PubMed

Publication types