## 3 Cardiovascular Diseases
### Atherosclerosis
#### 3.1.3 Formation of Fatty Streaks  
Endothelial stimulation, also known as type II endothelial activation, occurs in response to ox-LDL and involves the overactivation of the NF-xB inflammatory pathway within ECs. This leads to the increased expression of pro-inflammatory cytokines and chemokines (MCP-1 and IL-8), vascular (VCAM-1) and intercellular (ICAM-1) adhesion molecules for monocytes, and E-selectin and P-selectin [108; 119].  
The recruitment of monocytes from the bloodstream to the affected area of the endothelium is the first step in a cascade of subsequent events. Initially, monocytes are captured and roll along the endothelium surface, a process mediated by P-selectin, followed by their tight adhesion through their interactions with the endothelial VCAM-1 and ICAM-1. Chemokines, including CXCL1, CXCL2, CXCL4, and CCL5, present in the endothelial surface, activate monocytes as they roll, increasing their adhesiveness [108]. Subsequently,MCP-1 and IL-8 induce the transmigration of monocytes to the subendothelial space, where they mature and differentiate into macrophages, which can polarise into M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes, with the M1 predominating when the disease progresses. However, due to their sensitivity and plasticity, these macrophages can switch between M1 and M2 phenotypes in response to new signals [120].  
M1 macrophages produce huge amounts of pro-inflammatory cytokines and chemokines, as well as reactive oxygen and nitrogen species (RONS) such as \({}^{\bullet}\)NO and \({\rm O_{2}}^{\bullet-}\), contributing to an oxidative and inflammatory environment. They also express scavenger receptors, including CD36, SR-AI, and LOX-1, which recognise and internalise the modified forms of LDL, particularly ox-LDL. It is important to note that the activity of these receptors is not negatively regulated by the intracellular concentration of cholesterol, thus leading to a deregulated and exacerbated uptake of ox-LDL. Once internalised, ox-LDLs are degraded in lysosomes, and excess free cholesterol is transported to the endoplasmic reticulum (ER), where it is esterified by acyl-CoA acyltransferase (ACAT) into cholesterol esters, which are stored in lipid droplets in the cytoplasm or which are associated with the ER, a characteristic feature of foam cells [119; 121]. Cholesterol esters are hydrolys, and the resulting free cholesterol suffer efflux from macrophages to HDL via transporters like ABCA1. However, in the atherosclerotic lesions, the pro-inflammatory environment impairs these efflux systems. Therefore, the deregulated uptake of ox-LDL by macrophages, associated with the impaired efflux of cholesterol, promotes the formation and accumulation of foam cells, a key feature in atherosclerosis [122; 123].  
The excessive lipid uptake by macrophages sustains the inflammatory response, which is further exacerbated by the continuous activation of NF-kB signalling pathways by ox-LDL. This vicious cycle sustains EC activation, monocyte recruitment, and foam cell accumulation, ultimately leading to the development of fatty streaks [124]. In addition, VSMCs in the tunica intima can also internalise ox-LDL through their scavenger receptors (SR-A, CD36, LOX-1), further contributing to the growth of fatty streaks [125].  
Fatty streaks are an important precursor; however, they generally do not cause immediate clinical complications and may even spontaneously regress [119].