RRC ID 77535
Author Rivera Krstulovic, Catalina
Title Role of vascular Dnmt3a during adult homeostasis and disease-associated vascular re-activation
Abstract Vascular remodeling represents an adaptive mechanism to physiological alterations. However, when this mechanism is dysregulated, it results in pathological vascular re-activation. Pathological vascular re-activation is involved in tumor progression, cardiovascular diseases and chronic inflammatory conditions, and it may lead to impaired vascular function, formation of an aberrant vascular network and disease progression. Cancer is one of the leading causes of death worldwide. Similarly, obesity is a prominent risk factor for the development of cardiovascular diseases, which corresponds to a leading cause of mortality and morbidity worldwide as well. Since both pathological conditions are highly dependent on angiogenesis, the study of modulators of vascular re-activation and their particular role in tumor progression and obesity-derived cardiovascular impairment is crucial. During the last years, epigenetic modifications have emerged as critical regulators in the development and progression of various diseases including cancer, cardiovascular diseases, and neurological disorders. Consequently, epigenetic therapies have gone through clinical trials as potential treatments for cancer and other diseases, particularly those targeting DNA methylation. Previous studies from our group identified Dnmt3a as an epigenetic modifier in angiogenic neonatal endothelial cells. In neonates, the loss of Dnmt3a led to impaired vascular growth, suggesting Dnmt3a as a candidate to target in order to interfere with angiogenesis. DNMT3A contributes to the establishment, maintenance and remodeling of the DNA methylation landscape, but its role in endothelial cell disease-associated vascular re-activation has not been addressed so far. Therefore, by using a conditional mutant mouse that lacks Dnmt3a specifically in the endothelium (Dnmt3aiECKO), the present thesis was aimed at deciphering if the interference with Dnmt3a-dependent DNA methylation halts vascular re-activation during primary tumor development and obesity-induced inflammation, and if this interference would then impair vascular quiescence during health. The determination of the expression level of Dnmt3a in the disease-associated reactivated lung and heart endothelium revealed an induction of Dnmt3a expression after tumor growth and diet-induced obesity. Primary tumor experiments using the LLC tumor model in Dnmt3aiECKO mice revealed that Dnmt3a loss in the endothelium impairs tumor angiogenesis without affecting overall tumor development. In order to achieve obesity-induced inflammation, endothelial Dnmt3a deficient mice were fed a high fat diet for 8 weeks. The lack of Dnmt3a in the endothelium led to an alleviation of obesity-induced cardiac hypertrophy and a reduced vascular density. Moreover, increased cardiac fibrosis incidence and apoptosis, which impairs cardiac relaxation, led to diastolic dysfunction in Dnmt3aiECKO mice. In summary, the lack of endothelial Dnmt3a has a morphological and functional impact on the obese heart and Dnmt3a is required for obesity-induced cardiac hypertrophy. Lastly, I studied if the loss of Dnmt3a has an effect on the healthy quiescent endothelium. No major organ morphological changes in lung and liver were derived from the lack of Dnmt3a in the healthy endothelium. However, an enlarged heart was observed though there was no impact on cardiac function. A change in the expression of genes related to cell division in the heart, in addition to an up-regulation of aerocyte markers in the lung endothelium was observed after the loss of Dnmt3a in the homeostatic endothelium. In conclusion, this study demonstrated that the activity of endothelial Dnmt3a plays an important role in angiogenesis during pathological vascular re-activation, yet the healthy quiescent endothelium remains unaffected.
DOI 10.11588/heidok.00033951
Mice RBRC03731