Molecule | Target | Mechanisms | Refs |
---|---|---|---|
Barrier disruption | |||
Endothelial glycocalyx | Unknown | Loss of endothelial homoeostatic mechanisms Disruption of cell-cell and cell-matrix interactions Increased leucocyte adhesion | 12, 13 |
LPS | TLR4 | Intracellular calcium influx via DAG-induced TRPC6 channel activation Reduced FAK expression MLCK activation NF-κB induced inflammatory cytokine release | 41, 57, 120 |
Mechanical stretch | IL-6R | RhoA activation Expression of contractile proteins Cytokine release | 121–123 |
mtDNA | TLR9 | Intracellular calcium influx Cytokine release | 72 |
ROS | NADPH oxidase | Intracellular calcium influx and MLCK activation | 20, 21 |
Thrombin | PAR1 | Intracellular calcium influx and activation of MLCK and RhoA | 124, 125 |
TNF | TNFR1 | Promotion of NF-κB induced inflammatory cytokine release and upregulation of leucocyte ligands, for example, ICAM-1 | 17 |
Barrier enhancement | |||
ACE2 | Not applicable | Negative regulation of RAS via inactivation of angiotensin receptors Abrogation of Ang II signalling and activity | 89, 90 |
Adrenomedullin | CLR complex | Attenuation of MLCK phosphorylation Activation of protein kinase A, Promotes intercellular adherence | 115, 126 |
Ang1 | Tie2 | Adherens junction assembly via Rac1 activation Inhibition of NF-κB signalling Competitive inhibition of Ang-2-mediated barrier disruption | 65 |
ANP | NF-κB | Protects against LPS mediated NF-κB signalling Enhanced VE-cadherin localisation to AJ | 110, 111 |
HGF | MET | Activates Rac-dependent cytoskeletal rearrangement | 118, 119 |
IFNβ1a | CD73 | Upregulation of CD73-enhancing adenosine activity via adenosine dephosphorylation | 104, 127 |
Imatinib | c-Abl Arg PDGFR | Augmented Rac1 signalling Cytoskeletal rearrangement Inhibition of LPS-induced NF-κB signalling | 105, 109, 128, 129 |
S1P | S1PR1 | Stabilisation of AJs via Rac1 Inhibition of cofilin signalling enhancing TJ formation | 76, 130 |
Statins | HMG-coenzyme A reductase | Abrogation of VEGF signalling via RhoA inhibition and Rac1 activation | 97, 99, 100 |
AJ, adherens junction; Ang1/2, angiopoetin 1/2; ANP, atrial natriuretic peptide; Arg, Abl-related gene; CD73, cluster of differentiation 73; CLR, calcitonin receptor-like receptor; DAG, diacyglycerol; FAK, focal adhesion kinase; HGF, hepatocyte growth factor; HMG, 3-hydroxy-3-methyl-glutanyl; ICAM-1, intracellular adhesion molecule; IFNβ1a, interferon-β 1-α; IL-6R, interleukin-6 receptor; LPS, lipopolysaccharide; MET, hepatocyte growth factor receptor; MLCK, myosin light chain kinase; mtDNA, mitochondrial DNA; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor κB; PAR1, protease-activated receptor; PDGFR: platelet-derived growth factor receptor; RhoA, Ras homologue gene family, member A; RAS, renin-angiotensin system; ROS, reactive oxygen species; Tie2, tyrosine kinase receptor-2; TJ, tight junction; TLR4, toll-like receptor 4; TLR9, toll-like receptor 9; TNF, tumour necrosis factor; TNFR1, tumour necrosis factor receptor 1; TRPC6, transient receptor potential cation channel, member 6; S1P, sphingosine-1-phosphate; S1PR1, sphingosine-1-phosphate receptor 1; VE-cadherin; vascular endothelial cadherin; VEGF, vascular endothelial growth factor.