04 Sep 2006

Endothelial activation, dysfunction and damage - the key to thrombosis?

Prof. Gad Keren

Session number: 901000
Session title: Endothelial activation, dysfunction and damage - the key to thrombosis in vascular disease? - Bench to Bedside
Authors: Keren, G. Tel-Aviv, Israel

When I was a student of medicine (many years ago) I was always under the impression that the arteries and veins are inert tubular structures where blood is circulated through. This view has changed dramatically and remarkable research at the bench and in depth understanding of the functional properties of the endothelium and subendothelial structures has evolved. It allowed us to more clearly understand clinical presentations of acute and chronic cardiovascular and other diseases. This session provided a comprehensive insight into the basic functions of the endothelium and extended it to the potential use in patient evaluation and clinical management.

Dr. Tousoulis from Athens started the session by describing the properties of the endothelium as a vast tissue with billions of cells controlling complex metabolic pathways, blood flow vascular tone, interactions of blood cells, inflammatory properties, angiogenesis and vascular thrombosis. Special emphasis was given to endothelial function as an important marker of cardiovascular events. By showing a demonstrable case of the effect of Ach induced vasoconstriction from their cath lab he could present the complexity of controlling vascular tone by the endothelium. The various invasive and non-invasive methods to assess endothelial function were presented. The invasive methods are considered Gold standard and can be performed in the coronary vessels as well as in the brachial artery. Non-invasive methods include ultrasound, MRA, and plethysmography. Importantly, medical interventions such as therapy with statins, ACE inhibitors, or L-arginine were shown to improve endothelial function. However, my personal impression was that the non- invasive methods are still not fully ready to be used in clinical practice for individual patient clinical care and more research is needed.

Dr. Nickenig from Bonn led us into the depths of the mechanisms of endothelial integrity and dysfunction. The degeneration of the endothelial cell layer and its repair is an important issue. Apoptosis of the endothelial cell layer may influence endothelial function. Endothelial microparticles (EMP) are remnants of the endothelial cells that are found in the blood and are detected in disease states such as atherosclerosis, hypertension, diabetes mellitus and other high risk states. A correlation was found between the number of EMPs and endothelial dysfunction. Interestingly it seems that EMPs are functional since many active molecules reside within. Endothelial progenitor cells (EPCs) are involved in maintaining the integrity of the endothelial layer. These cells are heterogenous and a clear correlation exists between the number of EPCs and endothelial function, such that their numbers may even predict clinical outcome. Dr. Nickening suggested to use a vascular repair index by measuring EPCs and EMPs which in their research correlate to clinical outcome.

Dr. De Caterina from Chieti, led the way to discuss endothelial function, thrombosis with emphasis on atherothrombosis. In his view activation of the endothelium by noxious stimuli causes expression of various molecules, importantly VCAM-1 which has a role in attracting monocytes and lymphocytes that have a major role in atherosclerosis. Ox-LDL, advanced glycation products via their receptor (RAGE) induce a host of mechanisms and expression of MMPs, adhesion molecules, vasoconstrictive and prothrombotic factors (TF and TF microparticles) that lead to progression of the process of atherothrombosis.

The last lecture, by Dr. Lip from Birmingham provided an overview of the relationship between endothelial function, thrombosis, angiogenesis and atherogenesis. Rightfully he calls this “the vascular triad” . Fibrinogen levels and CRP rise in peripheral arterial disease. VEGF, angiopoieitin and sCD40L rise in hypertension and other clinical states and show the relationship between markers of inflammation, angiogenesis and thrombosis. Angiogenesis in the vasavasorum of atheroma can lead to plaque rupture and vascular events. After MI, VEGF angiopoietin 1 and Tie-2 rise in implicating the importance of angiogenesis in the early and late phases or post MI myocardial recovery, repair and remodelling. Conclusion The endothelium is a fascinating tissue, with intricate molecular mechanisms that control the basic processes of homeostasis. It is amenable to solid basic research that enhanced our understanding of pathophysiologic mechanisms underlying disease initiation and progression.

This led to the development of tools that allows for clinical evaluation of the functional properties of the vasculature and hopefully the identification of useful markers that will help in diagnosis, and evaluation of the response to therapy and interventions. Medications, currently in use and developed in the future as well as cell based therapies and mainly EPCs will be harnessed to the bedside clinical practice.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.