Perspectives in Circulation Today
The Endothelium: An Organ with Many Special Functions!
The endothelium historically was considered but a slick inner lining of the vessel wall. In recent years, there has been an explosion of research into its function and reaction to mechanical and humoral agents. The results of an internet search for references on the endothelium and various agents is graphed below:.
The above data were gained through a "Google" search for "References for endothelium and factor X". World-wide the endothelium and the factors operating on it were a major focus of research. The peak number of references was generally found around 1998. The number of references on nitric oxide then reached 1,670,000 (highest curve on graph) while the references on the effect of shear on the endothelium numbered 537,000. Interest in fibrinolysins peaked in 2000 when there were 47,400 references. In the last few years the number of references has decreased significantly. For the sake of comparison, in 1998 the number of references for "God" and "Sex" were respectively 1,880,000 and 3,430,000.
An incomplete list of the interactions of the endothelium with various agents is given in Table 1.
| Table 1: Functions of the Endothelium and the Endothelial Cells (EC) | |
| Containment of the blood | |
| Surface with minimal frictional drag on the movement of the blood and plasma volumes | |
| Response to hormones and vascular factors | |
 | Stimulation of endothelial production of nitric oxide by bradykinin, acetylcholine, vascular endothelial growth factor (VEGF). |
| Diminishing vasoactive effect of norepinephrine by metabolizing it, acting as a physical barrier to its overflow into the vessel lumen, inhibiting its release from adrenergic nerves.(Cohen and Weisbrod) |
| Increase release and degradation of Protein S (decrease in anticoagulant activity) induced by norepinephrine. |
| Norepinephrine stimulation of eNOS activity, VEGF mRNA synthesis and mitogenic activity.(Seya Y et al 2006) |
| Decrease in flow-mediated dilation and baroreflex sensitivity induced by cortisol (effect blocked by Metyrapone)(Broadley et al 2005) |
| Decrease in nitric oxide production, decreased brachial artery flow-mediated dilation and stiffening of the endothelium due to excess aldosterone; effect blocked by spironolactone |
| DHEA increases EC proliferation (and/or decreases programmed cell death) and function independent of estrogens and testosterone. |
| Statins: Lipid-independent effects: increases NO production, promotes re-endothelialization after arterial injury, inhibits inflammatory responses within the vessel wall and provides antithrombotic and antiproliferative effects. |
| Response to shear stresses | |
| Activation of VEGF receptor 2 and increased production of nitric oxide and prostacyclin. "Endothelium-derived hyperpolarizing factor" promotes vasodilation associated with shear independent of NO and prostaglandins. VEGF trap abolishes shear stress- and overload-dependent angiogenesis in skeletal muscle independent of nitric oxide. Mice lacking the gene encoding for Dystrophin have reduced shear-induced vasodilation. Shear stress is a key regulator for stem cell differentiation into EC, especially in endothelial progenitor cell differentiation, which can be used for vascular repair. Lowered mean shear stress and high amplitude shear stress are both essential conditions in plaque formation. Blocking shear-induced increases in nitric oxide decreases the increase in coronary artery blood flow produced by the aortic balloon (Toyota 1999). Low venular shear rates promote leukocyte-dependent recruitment of adherent platelets, the leukocytes and platelets potentially participating in inflammatory processes. |
| Recruitment of leukocytes | |
| Interleukin-1 (IL-1) and tumor necrosis factor (TNF). IL-1 induces synthesis of prostacyclin, platelet activating factor, thromboplastin and plasminogen activator inhibitor. Both IL-1 and TNF cause leukocyte adhesion to the endothelium. Platelet-endothelial cell adhesion molecule-1, a member of the immunoglobulin superfamily, is required for the transmigration of neutrophils across endothelial monolayers in vitro and required for neutrophil transmigration in vivo. |
| Recruitment of platelets | |
| Adherent platelets a central mediator in the homing of endothelial progenitor cells to vascular lesions contributing to repair and revascularization. (Langer HF et al 2007) |
| von Willebrand factor (VWF)is synthesized by EC in the presence of high shear forces. Platelet adhesion depends on the interaction between VWF and the platelet receptor glycoprotein Ib (GPIb); other adhesion molecules become involved. |
| Anaphylactic reactions | |
| Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is responsible for sepsis-induced hypotension and plays a major contributory role in the ensuing multiorgan failure. (Cauwels et al 2006) |
| Mechanical challenges to the Endothelium: | |
| Endarterectomy. |
| Embolectomy with Fogarty catheter. |
| Angioplasty |
| Stents |