Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

Abstract

Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future.

Keywords: atherogenesis; disturbed flow; hyperglycemia; hyperlipidemia; inflammation; platelet; platelet migration.

Figure 1

Disturbed flow-regulated platelets participate in the plaque formation. Disturbed flow activates endothelial cells (ECs), resulting in elevated expression of adhesion molecules and deposition of adhesion proteins. All these adhesion molecules and proteins interact with platelets via surface receptors, leading to platelet activation. Activated platelets recruit circulating leukocytes by P-selectin or other releasing inflammatory factors, therefore participating atherogenesis.

Figure 2

Platelets participate in atherosclerosis under hyperlipidemic conditions. Lipoproteins, such as low-density lipoproteins in plasma, trigger platelet activation by binding sites. Or monocytes engulf low-density lipoprotein (LDL)-containing apoptotic platelets and migrate under the inner membrane to differentiate into macrophages and foam cells. Subendothelial oxidized LDL further participates in atherosclerotic plaque formation by binding to scavenger receptor CD36 and LOX-1.

Figure 3

As an inflammatory mediator, platelets interact with ECs and leukocytes (mainly monocytes) to participate in the formation of atherosclerotic lesions. Pro-atherosclerosis factors can easily lead to platelet activation. The activated platelets express a variety of adhesion receptors. These receptors bind their matrix proteins (GPIb-vWF, GPVI-collagen, and GPIIb-IIIa-fibrinogen) to mediate platelet adhesion on ECs or leukocytes (P-selectin-PSGL-1 and Clec2-PDPN). Moreover, platelet activation releases a variety of inflammatory factors (cytokines, chemokines, growth factors, and others). These inflammatory mediators can also be induced and expressed in neighboring cells, such as monocytes/macrophages, neutrophils, and ECs, which in turn affected platelets. Blue arrow: the factor released by platelets interact with leukocytes; Black solid arrow: the rolling of leukocytes; Blue dotted arrow: activated leukocytes in turn affect platelets.