Endothelial cells : Dysfunction and repair mechanisms

University dissertation from Stockholm : Karolinska Institutet, Department of Clinical Sciences

Abstract: Endothelial cells (ECs) are crucial component of the normal vascular wall, providing an interface between the bloodstream and surrounding tissue of the blood vessel wall. Endothelial progenitors cells (EPCs) circulate in the blood and migrate to regions of the circulatory system with injured endothelium and ischemic tissues. The function of ECs/EPCs can be affected during pathological conditions, including vasculitides and atherosclerotic disease. In Wegener s granulomatosis (WG) circulating inflammatory endothelial cells (IECs) via production of soluble factors may sustain vascular damage by inducing EPC dysfunction. There was a markedly decreased of EPC colonies from peripheral blood samples of patients with active WG as compared with those who were in remission. Thus, these cells may have impaired functional capacity. In addition, during active WG disease the number of IEC was significantly higher as compared to WG patients in remission and normal controls. Moreover, IEC but not EPC expressed two novel endothelial cells inflammatory markers; vascular-adhesion protein-1 (VAP-1) and MHC class I-related chain A (MICA). Thus those markers can be used to distinguish inflammatory from progenitor endothelial cells. Using another vascular disease, the possible role of anti-endothelial cell antibodies (AECA) in patients with ischemic heart disease was investigated. AECA were significantly higher in patients with previous myocardial infarction. Plasma concentration of AECA IgG was positively correlated to the inflammatory risk factor C-reactive protein. Further, patients who got an invasive treatment had significantly higher levels of AECA as compared to patients with only medical treatment. The menstruation cycle (MC) was used as an angiogenic model. The numbers of EPC vary during the MC in relation to variations in blood levels of some angiogenesis growth factors (VEGF, G-CSF, GM-CSF, FGF, and SDF-1). Only the levels of the stromal cell-derived factor-1 (SDF-1) significantly varied during the menstrual cycle (MC), reaching the highest level at the mid-proliferative phase (day 5), and the levels were negatively correlated with the numbers of EPC colony-forming units (EPC-CFUs). Furthermore, the local expression of endometrial SDF-1 tended to be higher in the secretory than in the proliferative phase. The results point to SDF-1 as a novel mediator of EPC trafficking during the MC. Human fetal heart cardiac progenitor cells (fhCPCs) may have therapeutic potential for regenerative treatment of ischemic heart disease. Clonally isolated fhCPCs were found to be positive for the EPC markers (CD133+, CD34+ and KDR) and cardiac progenitor marker (c-kit+) with a suggested haematopoietic origin (CD45+). In matrigel, fhCPCs formed tubule-like and endothelial cell-like structures with a lot of pinocytotic vesicles and tight junction formations. After transplantation of these cells into the peri-infarcted region of SCID mouse heart, tubule-like structures inside the mouse heart were observed up to 12 days. In summary, the work of this thesis has shed light on the role played by EC and EPCs in health and disease. During pathological conditions (WG, atherosclerosis) the functions of ECs/EPCs are affected and may worsen the progression of the disease by impairing repair mechanisms of the blood vessels. SDF-1 has a potential role during angiogenesis and EPC activity. Expanded CPCs may have the capacity to restore ischemic cardiac tissue.

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