Excessive erythrocytosis compromises the blood–endothelium interface in erythropoietin‐overexpressing mice

Abstract

Non-technical summary Elevated systemic haematocrit (Hct) increases cardiovascular risk, such as stroke and myocardial infarction. One possible pathophysiological mechanism could be a disturbance of the blood-endothelium interface. It has been shown that blood interacts with the endothelial surface via a gel-like layer (the 'glycocalyx' , or 'endothelial surface layer' -ESL) that modulates various biological processes, including inflammation, permeability and atherosclerosis. However, the consequences of an elevated Hct on the functional properties of this interface are incompletely understood. In a transgenic mouse (tg6) model exhibiting systemic Hct levels of about 0.85 the glycocalyx/ESL was nearly abolished. The corresponding increase in vessel diameter had only minor effects on peripheral flow resistance. This suggests that the pathological effects of elevated Hct may relate more strongly to the biological corollaries of a reduced ESL thickness and alterations of the blood-endothelium interface than to an increased flow resistance.Abstract Elevated systemic haematocrit (Hct) increases risk of cardiovascular disorders, such as stroke and myocardial infarction. One possible pathophysiological mechanism could be a disturbance of the blood-endothelium interface. It has been shown that blood interacts with the endothelial surface via a thick hydrated macromolecular layer (the 'glycocalyx' , or 'endothelial surface layer' -ESL), modulating various biological processes, including inflammation, permeability and atherosclerosis. However, the consequences of elevated Hct on the functional properties of this interface are incompletely understood. Thus, we combined intravital microscopy of an erythropoietin overexpressing transgenic mouse line (tg6) with excessive erythrocytosis (Hct 0.85), microviscometric analysis of haemodynamics, and a flow simulation model to assess the effects of elevated Hct on glycocalyx/ESL thickness and flow resistance. We show that the glycocalyx/ESL is nearly abolished in tg6 mice (thickness: wild-type control: 0.52 μm; tg6: 0.13 μm; P < 0.001). However, the corresponding reduction in network flow resistance contributes <20% to the maintenance of total peripheral resistance observed in tg6 mice. This suggests that the pathological effects of elevated Hct in these mice, and possibly also in polycythaemic humans, may relate to biological corollaries of a reduced ESL thickness and the consequent alteration in the blood-endothelium interface, rather than to an increase of flow resistance.

Obesity-related increase in whole blood viscosity includes different profiles according to fat localization

“…Classically, it was believed that it induced thrombosis via a circulatory impairment resulting from hyperviscosity, according to Poiseuille's law. Recently, elegant experimental and modelling work by the group of Fries [35] has shown that increased hematocrit reduced the thickness of the intraluminal cell free layer, a mechanism that may trigger the atherogenetic process [44]. Therefore, high hematocrit may be deleterious for vascular health via its effects on the glycocalyx rather than its effects on blood flow which seem to have been overestimated.…”

The glycocalyx and its significance in human medicine

“…Elevated systemic haematocrit increases the risk of stroke and myocardial infarction. Richter et al [42] used an erythropoietin overexpressing transgenic mouse line (tg6) with a haematocrit of 0.85 to assess the effects of elevated haematocrit on GCX thickness and observed that the GCX is nearly abolished in tg6 mice. This suggests that the pathological effects of elevated haematocrit in these mice, and possibly in polycythemic humans, relates to a reduced GCX thickness and the consequent alteration in the blood-endothelium interface.…”

Elevated haematocrit – when too much of a good thing wreaks havoc on the endothelial surface layer

“…Because of the obvious link between elevated Hct and increased blood viscosity, it is generally thought that the increased cardiovascular risk is due to pathological changes in haemodynamics, often resulting in peripheral ischaemia, which lead to increased total peripheral resistance and arterial blood pressure. In an article in a recent issue of The Journal of Physiology , Richter et al (2011) suggest that the origin of cardiovascular problems associated with chronically elevated Hct lies rather with interactions between the RBCs and the glycocalyx or endothelial surface layer (ESL).…”

“…The animal model used in the study of Richter et al (2011) was that of a transgenic mouse (tg6) line which overexpressed human erythropoietin (Vogel & Gassmann, 2011). The systemic Hct of the tg6 mice was 85% compared with 46% for the control mice.…”

“…Under normal conditions the thickness of this gel‐like structure varies between 0.4 and 1.2 μm depending on several factors. The thickness of this layer has been quantified by several different approaches, and in the study of Richter et al (2011), the microviscometric method developed by Damiano et al (2004) was employed to analyse velocity profile data collected using the μ‐PIV technique. In the μ‐PIV method, the cross‐sectional velocity distribution of 0.5 μm diameter fluorescent microspheres was measured and interpreted by the microviscometric method, which provided calculated data on a variety of key microhaemodynamic variables.…”