**5. Conclusions**

Atherosclerosis represents a multifactorial disease mainly driven by arterial hypertension, hypercholesterolemia and diabetes mellitus, which, through the stenosis and occlusion of arteries, leads to organ ischemia and thus constitutes a main driver of mortality worldwide. The three main contributors to the development of atherosclerosis can originate from similar sources, such as sedentary lifestyle, western diet and obesity and exerted damage to the vessel wall via distinct but overlapping pathomechanisms. The hallmark of vascular alterations elicited by all three disease entities lies in the endothelial dysfunction seen in atherosclerosis, which is largely driven by an increase in endothelial activation with an elevated uptake of lipids, namely low-density lipoproteins, into the vascular wall. This process triggers the production of reactive oxygen species as well as the attraction of macrophages to the site of plaque formation, leading to their transformation into foam cells. All of those pathological alterations can enter into a positive feedback loop aggravating the development of plaque formation. One additional component in this disease progression is the proliferation of vascular smooth muscle cells, which can participate in the uptake of oxidized LDL and can also transform into foam cells, which serve as a source for inflammatory cytokines, attracting more macrophages. Herein lies one key difference between the macrocirculation (e.g., larger arteries) and the microcirculation exemplified by capillaries. Capillaries are surrounded not by vascular smooth muscle cells but by pericytes, a cell type related to vascular smooth muscle cells but with distinct functions in the vascular unit. Unlike vSMCs, pericytes react to the pathological stimuli elicited by hyperglycemia and hypercholesterolemia with a detachment from the underlying endothelium, resulting in further endothelial activation and apoptosis. This leads to capillary rarefication and reduced blood flow due to a decrease in capillary surface area.

Here, we highlighted potential therapeutic targets to improve microvascular dysfunction, namely by expressing proangiogenic growth factors and pericyte chemoattractants, either combined in one signaling molecule (as is the case for Thymosin β4) or in a cooperative fashion (such as the combined overexpression of VEGF-A and PDGF-B), all of which are mediated by a recombinant adeno-associated viral vector mediated overexpression, or the short-term burst expression of VEGF-A alone in the form of VEGF-A encoding modified RNA.

Taken together, the microcirculatory changes during atherosclerosis warrant further investigation and represent a worthwhile topic for additional studies.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
