Heart and lung function work in partnership to maintain cardiovascular and tissue homeostasis. Endothelial (EC)-specific transcription factor ERG is a master regulatory of EC lineage and homeostasis expressed in all vascular beds. We have shown that loss of ERG expression leads to endothelial dysfunction and tissue fibrosis in mouse. Furthermore, we have established ERG loss as a hallmark of patients with chronic disease, such as atherosclerosis and end-stage liver disease. In this study we aimed to determine the functional impact of chronic EC dysfunction on the cardiopulmonary system.
Methods 6-week-old VEC-iCre Erg-fl/fl mice were treated with tamoxifen i.p. to induce EC-specific deletion (ErgiEC-KO); mice were profiled longitudinally for 30 days compared to littermate control mice (Ergfl/fl). We assessed cardiac function by electrocardiography (ECG), recorded in conscious mice twice a week using the ECGenie platform, and echocardiography (Echo) at day 14 and 30. Tissue structure and endothelial profiling was assessed by immunohistochemistry in both heart and lung tissue. In a second set of experiments we treated mice ErgiEC-KO with tamoxifen for 14 days prior to transverse aortic constriction (TAC) to induce elevated cardiovascular load.
Results ECG measurements revealed that ErgiEC-KO had significantly reduced heart rate and lengthened cQT interval occurring from one week after ERG-deletion. Echo showed significantly reduced ejection fraction and fractional shortening in ErgiEC-KO. Tissue profiling at day 30 post-tamoxifen found a significant increase in ErgiEC-KO heart/body weight ratio. Immunohistochemistry revealed significant cardiomyocyte hypertrophy together with increased SMA and pSMAD3 in all regions of the heart. We observed significant thickening of the right ventricular wall, in line with signs of inflammation, fibrosis and haemorrhage in lung tissue from ErgiEC-KO. Interestingly, phenotypic changes in pulmonary microvascular EC were homogeneous while cardiac microvascular EC had geographical and subset-specific variations. TAC surgery resulted in all ErgiEC-KO reaching endpoint within 28 days (n=5) with significant heart dilation and reduced cardiac function. Notably all ErgiEC-KO exhibited severe inflammation and loss of lung structure. (Figure 1)
Conclusion Systemic deletion of EC-specific ERG significantly influences the microvascular profile, structural integrity and function of cardiopulmonary system. This study highlights that impaired EC functional can rapidly influence ventricular repolarisation and cardiac function. Furthermore, we uncover that chronic EC dysfunction in ErgiEC-KO causes systemic mechanisms and organotypic phenotypes affect the heart and lung emphasizing the role of the endothelium in regulating cardiovascular function.
Conflict of interest No
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