Inflammatory Mediators in Atherosclerotic Vascular Remodeling

Abstract

Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.

Sex‐specific and hormone‐related differences in vascular remodelling in atherosclerosis

“…Furthermore, oestrogen decreases the expression of pro‐inflammatory TNFα (Figure 1 and Table 1). 47 TNFα is a cytokine implicated in promoting vascular remodelling by increasing adhesion molecule expression on ECs as well as EC permeability, upregulation of matrix degradation and VSMCs proliferation 48 . In line with this, ovariectomized female control rats had a significant increase in serum TNFα compared with ovariectomized animals with oestrogen‐replacement treatment (oestrogen pellet:1.5 mg/pellet).…”

“…However, due to the thick fibrous cap, vascular integrity remains intact, and the plaque remains stable 114 . In addition, atherosclerotic plaques in female humans are characterized by a larger necrotic core compared with males while, in female mice, oestrogen decreases adhesion molecule expression, decreases neutrophil infiltration and pro‐inflammatory cytokines such as TNFα, IL‐1β and IL‐6 secretion and therefore halting atherosclerosis 6,47,48 . After menopause, oestrogen level decreases and its vasoprotective effects are lost 37–40 .…”

“… 38,49 Two hours following balloon injury, 17β‐estradiol‐treated ovariectomized rats showed a significant decrease in mRNA expression of the adhesion molecules ICAM1, VCAM1 and P‐selectin as well as a decrease in pro‐inflammatory IL‐1β and IL‐6 in injured carotids arteries 38 . IL‐1β and IL‐6 are both pro‐inflammatory cytokines that promote vascular remodelling by increasing EC dysfunction, leukocyte recruitment to the intima, VSMC migration and proliferation and lesional collagen deposition 48 . However, 24 h postinjury, the significant decrease remained only for P‐selectin and IL‐6 suggesting that oestrogen especially helps to reduce early inflammatory processes 38 .…”

“…114 In addition, atherosclerotic plaques in female humans are characterized by a larger necrotic core compared with males while, in female mice, oestrogen decreases adhesion molecule expression, decreases neutrophil infiltration and pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 secretion and therefore halting atherosclerosis. 6,47,48 After menopause, oestrogen level decreases and its vasoprotective effects are lost. [37][38][39][40] Male (right): In male humans, plaque rupture is the main cause of thrombus formation induced by fibrous cap burst leading to physical disruption of the vascular wall integrity and to the exposure of highly thrombotic components from the plaque to the blood and to a so-called 'red' thrombus formation.…”

Baiying qingmai formulation ameliorates thromboangiitis obliterans by inhibiting HMGB1/RAGE/NF-κB signaling pathways

“…For instance, HMGB1 stimulates the secretion of inflammatory cytokines including TNF-α, IL-6, IL-1α, and IL-8 by monocytes and neutrophils ( Ge et al, 2021 ). TNF-α is an important regulator of the inflammatory response that upregulates the expression of endothelial adhesion molecules, leading to the adhesion of monocytes to the endothelium ( Evans et al, 2022 ). Therefore, HMGB1 maintains positive feedback with respect to the secretion of inflammatory cytokines.…”