Vascular related pathologies in cardiovascular disease and cancer

University dissertation from Stockholm : Karolinska Institutet, Dept of Medicine, Solna

Abstract: Cardiovascular disease (CVD) and cancer are the leading causes of death worldwide. A damaged endothelium is one of the factors contributing towards these diseases. This thesis focused on understanding the implications of alterations to the physiological endothelium resulting in pathologies related to vascular disease and cancer metastasis. Functional healing response occurs in the diseased vessel wall aimed at restoring the vessel after an injury. Existing studies state that vascular progenitor cells contribute to the injured vasculature and aid in the repair process. Yet the mechanisms underlying the amalgamation of the cells to the endothelium, their origin and functions have not been clear. Through Study 1 using animal models of arterial injury, we examined the role of bone marrow derived cells in arterial repair and the mechanisms behind it. We observed that bone marrow-derived cells, helped in the initial stages of arterial injury and were subsequently eliminated from the artery wall. They localized in the arterial intima and most them were of endothelial phenotype. Additionally, bone marrow-derived cells did not fuse with the intima but could differentiate into vascular cells. This helped them adjust in the vessel wall and meet the needs of their new microenvironment. Fascinatingly, local delivery of bone marrow-derived endothelial cells to the sites of arterial injury caused a 1.4-fold decrease of the intimal lesion area. These results define the role of BM derived endothelial cells in the development of intimal lesions post vascular injury and this information contributes to the existing understanding of the pathogenesis of intimal hyperplasia. Hemodynamic forces are a cause of a dysfunctional endothelium. A turbulent blood flow could result in vascular disease. Studies have shown that red blood cell distribution (RDW) width as a risk factor for death in cancer and CVD. RDW is one of the haematological parameters commonly reported as part of a complete blood count An RDW higher than normal is termed as anisocytosis. Anisocytosis has been traditionally used, in combination with the red blood cell corpuscular volume, to diagnose chronic inflammatory status in the body. It has been never studied before if anisocytosis is just factor that reflects chronic inflammation in the body, or is factor that directly affects it. Hence in Study 2, we hypothesized that anisocytosis leads to changes in blood flow affecting interaction between blood and vascular endothelium at the bifurcation of arteries. We found that a high RDW is a predictive factor for the interaction between cellular components of blood and vascular wall. These interactions can lead to increased inflammation in the vessels and initiation of thrombosis. Put together, we suggest that anisocytosis measured by RDW is a predictive factor of vascular diseases. Cancer metastasis is one of the major causes of mortality and arises also due to a damaged endothelium. In Study 3 we investigated the role of murine cytomegalovirus(MCMV) in colon cancer progression using MCMV infected and non-infected animal models. Our results indicate that MCMV did not affect tumor growth but increases the incidence of metastasis to the lungs. Additionally, using microarray analysis we found cytokeratins 1, 2 and 14 to be upregulated 100 times in the infected models compared to the non-infected. We speculate that in our case metastasis is mediated possibly through a cytokeratin mediated pathway. The mechanism for dissemination is under investigation. In Study 4, we investigated the effect of C/EBPβ on metastasis and the relationship between C/EBPβ expression and overall survival of breast cancer patients. We found that decrease in C/EBPβ expression was related to shorter overall survival of breast cancer patients. Loss of C/EBPβ also, affected tumor growth, morphology and lung metastasis in murine 4T1 breast cancer model. Furthermore, inhibition of C/EBPβ resulted in an augmented expression of MHCII and CD45+, CD3+ and CD4+ lymphocytes accumulation in the tumors. Additional experiments established the role of inflammation in C/EBPβ-mediated metastasis formation.

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