Atherosclerosis and the Capillary Network; Pathophysiology and Potential Therapeutic Strategies

Abstract

Atherosclerosis and associated ischemic organ dysfunction represent the number one cause of mortality worldwide. While the key drivers of atherosclerosis, arterial hypertension, hypercholesterolemia and diabetes mellitus, are well known disease entities and their contribution to the formation of atherosclerotic plaques are intensively studied and well understood, less effort is put on the effect of these disease states on microvascular structure an integrity. In this review we summarize the pathological changes occurring in the vascular system in response to prolonged exposure to these major risk factors, with a particular focus on the differences between these pathological alterations of the vessel wall in larger arteries as compared to the microcirculation. Furthermore, we intend to highlight potential therapeutic strategies to improve microvascular function during atherosclerotic vessel disease.

Keywords: atherosclerosis; capillary; endothelial cells; pericyte; rAAV.

Figure 1

(A) The healthy circulatory system is characterized by minimal lipid accumulation in larger arteries and an overall low state of endothelial activation, leading to low levels of ROS production and leukocyte recruitment. (B) Upon prolonged exposure to the atherosclerotic risk factors arterial hypertension, hypercholesterolemia and diabetes, endothelial cells experience constant activation enhancing leukocyte recruitment, oxidative stress and loss of pericytes in the microcirculation, leading to capillary rarefication, limiting the potential blood flow through the now sparse capillary network. (C) Even after mechanical revascularization, via bypass operations or percutaneous angioplasty, the capillary rarefication remains, continuously limiting blood flow, thus hindering the recovery of the ischemic tissue and leaving newly opened vessels susceptible for restenosis and stent thrombosis. Here, strategies to improve capillary density, and thus, microcirculatory flow, appear to be worthwhile therapeutic targets in the treatment of atherosclerosis currently not yet addresses.

Figure 2

Effect of in vivo genome editing via rAAV and Cas9 mediated deletion of exon 51 of Duchenne muscular dystrophy on the vascularization and macrophage recruitment in the heart and upper and lower hind limb in DMDΔ52 pigs. (A) staining for CD31 positive endothelial cells highlights a significant decrease in capillary density in pigs suffering from Duchenne muscular dystrophy which ins ameliorated in pigs receiving Cas9 mediated Exon 51 deletion thus restoring dystrophin expression. (B) Similarly, edited DMD pigs display an amelioration of pericyte loss seen in dystrophin deficient pigs. (C) Lastly, the reduction in both endothelial cells as well as pericytes in dystrophin deficient pigs is accompanied by an increased recruitment of CD68 positive macrophages into the tissue, similarly to the recruitment seen in atherosclerotic states, which is again reversed upon normalization of dystrophin expression (*p < 0.05 versus wild type and DMD+rAAV.Cas9, error bars are given as SEM).