Introduction: ERK5 is a member of the MAPK protein family involved in several crucial cellular functions, including cell proliferation, differentiation, and migration. Unlike the rest of the MAPK family members, ERK5 can respond to a multitude of growth factors and cytokines as well as common stressors including hypoxia, osmolarity, ROS and blood flow. Mice lacking Erk5 are embryonic lethal due to cardiovascular defects, while deletion of Erk5 in adult mice results in wasting syndrome that involves endothelial destabilization. To date, several ERK5 downstream targets have been described, however, there is no well-established mechanism detailing the role of ERK5 in endothelial integrity and its potential roles in disease mechanisms.
Hypothesis: We set out to identify endothelial based ERK5 targeted pathways that regulate cardiovascular homeostasis and disease.
Methods/Results: Using tamoxifen inducible, endothelial specific knockout mice of Erk5 (Erk5ECKO) we demonstrate that loss of Erk5 in the endothelium is lethal within 25 days. The mice develop worsening pulmonary edema and pulmonary hemorrhage, and serial echocardiograms demonstrate markedly increased heart size and thickness, with hyperdynamic left ventricular ejection fraction. Using in vitro techniques, we show that loss of ERK5 in endothelial cells promotes increased expression of ANGIOPOIETIN 2 (ANGPT2), a TIE2 receptor ligand, which is found increased in disease contexts such as sepsis and acute lung injury, and is known to induce endothelial permeability via adherens junction destabilization. We further show that endothelial ERK5 is required for phosphorylation and subsequent degradation of YAP, a Hippo pathway member known to promote ANGPT2 expression. Finally, using tamoxifen inducible, endothelial specific knockout mice of both Erk5 and Yap we show that endothelial loss of Yap improves the survival and cardiac phenotypes of Erk5ECKO mice.
Conclusions: Overall, our findings provide critical mechanistic knowledge on endothelial destabilization due to impaired ERK5 signaling, while setting forth new biomarkers and therapeutic candidates for diseases that involve endothelial dysfunction.