Mathematical modeling of vascular endothelial layer maintenance: the role of endothelial cell division, progenitor cell homing, and telomere shortening

Abstract

Maintenance of the endothelial cell (EC) layer of the vessel wall is essential for proper functioning of the vessel and prevention of vascular disorders. Replacement of damaged ECs could occur through division of surrounding ECs. Furthermore, EC progenitor cells (EPCs), derived from the bone marrow and circulating in the bloodstream, can differentiate into ECs. Therefore, these cells might also play a role in maintenance of the endothelial layer in the vascular system. The proliferative potential of both cell types is limited by shortening of telomeric DNA. Accelerated telomere shortening might lead to senescent vascular wall cells and eventually to the inability of the endothelium to maintain a continuous monolayer. The aim of this study was to describe the dynamics of EC damage and repair and telomere shortening by a mathematical model. In the model, ECs were integrated in a two-dimensional structure resembling the endothelium in a large artery. Telomere shortening was described as a stochastic process with oxidative damage as the main cause of attrition. Simulating the model illustrated that increased cellular turnover or elevated levels of oxidative stress could lead to critical telomere shortening and senescence at an age of 65 yr. The model predicted that under those conditions the EC layer could display defects, which could initiate severe vascular wall damage in reality. Furthermore, simulations showed that 5% progenitor cell homing/yr can significantly delay the EC layer defects. This stresses the potential importance of EPC number and function to the maintenance of vascular wall integrity during the human life span.

Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability

“…Once the atherosclerotic process starts, the extensive oxidation of LDL in the intima could lead to mitochondrial damage and ROS production in endothelial cells [34], further promoting cellular senescence directly or indirectly by an increased cell death and thus increased cell turnover. Mathematical modeling of the dynamics of endothelial cell damage, repair and telomere shortening suggests that in humans, at an age of 65 years, approximately 2-5% of the vascular endothelial cells are senescent [17]. …”

“…Some of these changes, such as decreased eNOS activity and decreased NO production [11,15], reduction in mitochondrial membrane potential [5] and increase of ICAM-1 levels [11,16], directly correlate with endothelial dysfunction. Although in general in vivo endothelial turnover is low [17], in atherosclerotic-prone areas [18,19] -at bifurcations or other areas of vascular transition- the endothelial cell turnover is expected to be increased because of chronic injury due to changes in shear. Senescent endothelial cells have been identified in vivo [20], specifically at sites of atherosclerotic lesions [10,11].…”

Quantifying the Evolution of Vascular Barrier Disruption in Advanced Atherosclerosis with Semipermeant Nanoparticle Contrast Agents

“…Increased endothelial permeability is an early preclinical feature of barrier dysfunction and has been studied with the use of tracer agents (<5 nanometers) such as horse radish peroxidase, radiolabeled albumin, or various permeable dyes [7], [17]. Over time, endothelial cell senescence ensues, leading to local inflammatory responses, compromised endothelial regenerative potential, and ultimately apoptosis and endothelial denudation [18], [19], [20], [21], [22]. Yet the aforementioned methods for studying endothelial function do not specifically depict barrier disruption in vitro or in vivo because they generally reflect paracellular leakage in early stages of disease, as distinguished from later stage endothelial disruptions (erosion, micro-tears, etc.)…”

Relation between the frequency of CD34+ bone marrow derived circulating progenitor cells and the number of diseased coronary arteries in patients with myocardial ischemia and diabetes

“…Reports suggest that risk factors and a genetic predisposition together induce inflammatory processes that leads to cell damage and impairs regeneration within the vessel wall [12,13]. Since resident endothelial cells infrequently proliferate, [14] it has been postulated that there are other sources of vascular replenishment in response to continuous damage [15]. Circulating progenitor cells derived from bone marrow circulate in the peripheral blood and have been implicated in neoangiogenesis after tissue ischemia has occurred [16-19].…”