Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1-directed novel therapeutics

Abstract

Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1-directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1-directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development.

Keywords: Anti-VCAM-1 therapy; Atherosclerosis; Cardiovascular disease; Inflammation; VCAM-1.

Graphical Abstract

Figure 1

Summarizing the rationale of VCAM-1–directed therapies for the treatment of atherosclerosis. VCAM-1–inhibiting drug candidates can be broadly categorized based on two pharmacological mechanisms: (a) drugs that suppress VCAM-1 expression and (b) drugs that inhibit the VCAM-1/VLA-4 interaction involved in endothelial-monocyte attachment.

Figure 2

A conceptual diagram illustrating pathological monocyte recruitment during atherosclerosis. The accumulation of LDL infiltrates within the sub-intimal space activates vascular ECs to up-regulate their expression of CAMs. These CAMs mediate firm monocyte–endothelial interactions that facilitate cell adhesion and transmigration across the vascular endothelium. Once within the sub-endothelial space, recruited monocytes differentiate into macrophages, which uptake excess LDL at the expense of transforming into lipid-engorged foam cells. Additionally, macrophages secrete cytokines to establish a positive feedback loop of continual monocyte recruitment and accumulation. Eventually, transformed foam cells amalgamate to form an atheromatous plaque.

Figure 3

Binding interactions between VCAM-1 on vascular ECs and VLA-4 integrin on circulating monocytes during vascular inflammation. (1) VCAM-1 expression is induced on activated ECs in response to pro-inflammatory conditions. (2) Circulating monocytes express the low-affinity conformation of VLA-4, which can only bind to domain 1 of VCAM-1. The resultant VCAM-1/VLA-4 interaction mediates the weak binding associated with rolling leucocyte adhesion. (3) The high-affinity conformation of VLA-4 is activated in response to inflammation and can bind both Domains 1 and 4 of VCAM-1. This stronger version of the VCAM-1/VLA-4 interaction is responsible for the firm monocyte-endothelial adhesions necessary for monocyte arrest and transmigration.

Figure 4

Intra-cellular signalling pathways involved in VCAM-1–mediated transmigration across the vascular endothelium. Clustering interactions between VCAM-1 on activated ECs and VLA-4 on circulating monocytes initiate Ca²⁺ flux and Rac1 activation, both of which consequently activate NOX2. NOX2 generates H₂O₂ from O₂ to activate MMPs and PKCα, which activates PTP1B and ERK1/2. PTP1B and ERK1/2 in conjunction stimulate the disassembly of VE-cadherin from adherens junctions. The cumulative effect of these molecular pathways induces localized weakening of cell-to-cell junctions and gap formation to facilitate cell diapedesis from the vessel lumen into the sub-endothelial space.

Figure 5

Comparing monocyte attachment following selected peptide- and antibody-based treatments targeting the VCAM-1/VLA-4 interaction. U937 adhesion to isolated perfused carotid arteries of ApoE^−/− mice was visualized using composite epifluorescence videomicrography. (A–F) Treatment with (A) 3-(N-morpholino)propanesulfonic acid (MOPS) buffered salt solution, (B) non-blocking control mAb Lia, (C) anti-VLA-4 mAb HP1/3, (D) anti-VCAM-1 mAb MK-2.7, (E) ILDV peptide, and (F) anti-VLA-4 mAb HP1/2. (G) The accumulation of monocytes was subsequently quantified and plotted. The graphed data illustrate that ILDV peptide, MK-2.7 mAb, and HP2/1 mAb significantly reduced monocyte accumulation compared to MOPS and non-blocking mAb Lia controls (Huo et al.).