ARDS
Microvascular Leakage as Therapeutic Target for Ischemia and Reperfusion Injury
Kloka JA, Friedrichson B, Wülfroth P, Henning R, Zacharowski
This review focuses on microvascular leakage as a potential therapeutic target for ischemia and reperfusion injury, a common complication in revascularization therapies. Despite significant laboratory advances, clinical translation has been limited. We advocate for multi-target approaches that interfere with pathophysiological pathways, with a renewed emphasis on microvascular dysfunction, particularly microvascular leakage. Such strategies may offer novel insights and enhance treatment efficacy for these complex conditions.
Figure 1
Ischemia/reperfusion injury affects the myocardium and the microvasculature. Restoration of blood flow leads to production of reactive oxygen species, normalization of pH, release of calcium and reduced availability of nitric oxide in the cardiomyocyte. These biochemical changes lead to myofibril contracture and MPTP opening in mitochondria, and eventually to necrosis, apoptosis or necroptosis. Endothelial barrier disruption leads to extravasation of water and proteins from the coronary vessels and edema, capillary compression and microvascular obstruction. Tissue inflammation is a consequence of leukocyte diapedesis.
Figure 2
(A) under resting condition, the endothelial barrier is stabilized by attachment of VE-cadherin to thick cortical bands of actin fibers. (B) upon stimulation with danger signals, the actomyosin cytoskeleton is re-arranged with the formation of transcellular stress fibers. The contraction of myosin causes a disruption of the homotypic complexes of VE-cadherin and an opening of the adherens junction. (C) Rho A and Rac 1 play a central role in this process. Upon GPCR activation by various ligands, RhoA is transformed into its GTP binding form, which can activate Rho-associated kinase (ROCK), which phosphorylates myosin light chain leading to actomyosin contraction. The RhoA activity is functionally opposed by Rac1 (modified from [48]).
Kloka JA, Friedrichson B, Wülfroth P, Henning R, Zacharowski K. Microvascular Leakage as Therapeutic Target for Ischemia and Reperfusion Injury. Cells. 2023 May 9;12(10):1345. DOI: 10.3390/cells12101345. PMID: 37408180; PMCID: PMC10216082.