Vascular adhesion molecule (VAM) is a generic term to describe a family of molecules, which plays crucial roles in mediating cell-to-cell cooperation and cell-to-extracellular matrix interactions, especially in the processes of inflammation and regulation of immune cell activation and migration. VAMs contain a large number of molecules, which include Immunoglobulin Superfamily (IgSF), ICAMs (Intercellular Adhesion Molecules), PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1), also referred to as CD31, MadCAM-1 (Mucosal Vascular Addressin Cell Adhesion Molecule-1), Selectin, E-selectin, Integrin, and Cadherin. In the 1980s, scientists began to recognize that the interactions between cells, as well as between cells and the extracellular matrix, play pivotal roles in many physiological and pathological processes. This realization led to systematic research on cell adhesion molecules. The discovery of VAMs has been a progressive journey involving advancements in molecular biology, immunology, and cellular biology. For instance, P-selectin was discovered in the late 1980s, and was identified on the surfaces of activated endothelial cells and platelets. This protein was initially recognized for its role in mediating the rolling of leukocytes on the endothelium during inflammation [1]. Also discovered in the late 1980s, E-selectin was identified as a cytokine-inducible adhesion molecule expressed on endothelial cells and was shown to mediate leukocyte rolling and was pivotal in early inflammatory responses [2]. ICAM-1 was found to be upregulated on endothelial cells in response to inflammatory cytokines in the 1980s. This molecule plays a critical role in firm adhesion and transmigration of leukocytes [3]. Integrins were characterized in studies through the late 1980s and early 1990s. Specific integrins, such as LFA-1 (αLβ2), were identified for their roles in leukocyte adhesion through interactions with ICAMs [4]. The identification of PECAM-1 was facilitated by the development of monoclonal antibodies. In 1989, researchers led by Peter Newman and colleagues generated a monoclonal antibody (anti-CD31) that specifically binds a protein expressed on the surfaces of platelets, endothelial cells, and leukocytes. This antibody was instrumental in isolating and characterizing the molecule later known as PECAM-1 [5].
In the most recent article published in Cardiovascular Innovations and Applications, Sun et al. have used Mendelian randomization to evaluate the causal relationships of PECAM-1 in several cardiovascular diseases (CVDs) [6]. The researchers first identified six SNPs of PECAM-1, and subsequently applied several analysis methods. High levels of PECAM-1 have been reported to potentially reduce the risk of myocardial infarction and coronary heart disease. However, the study did not find causal relationships of PECAM-1 in hypertension, any phenotype of heart failure, stroke, or atrial fibrillation. Additionally, to ensure the robustness of the results, the researchers conducted several complementary tests. The results have continued importance, because this study was the first to use Mendelian randomization to evaluate the causal relationship of PECAM-1 in nine CVDs. The study has illustrated that PECAM-1 can serve as a biomarker for several CVDs.
VAMs have critical roles in various diseases by mediating interactions between endothelial cells and leukocytes, facilitating leukocyte trafficking, and maintaining vascular integrity. Their dysregulation has been implicated in several pathological conditions. For example, in atherosclerosis, VAMs such as ICAM-1, VCAM-1, and E-selectin are upregulated on endothelial cells in response to inflammatory stimuli. This upregulation promotes the adhesion and transmigration of leukocytes to and through the arterial wall, thus contributing to plaque formation and progression. Elevated levels of these adhesion molecules correlate with increased risk of cardiovascular events [7]. In rheumatoid arthritis, increased expression of ICAM-1, VCAM-1, and E-selectin in the synovial tissue enhances recruitment of inflammatory cells to the joints, thus exacerbating joint inflammation and damage. Therapeutic strategies targeting these molecules aimed at decreasing inflammation and improving clinical outcomes have been explored. Tumor cells often hijack VAMs, thus facilitating adhesion to the vascular endothelium and subsequent extravasation into distant tissues. For instance, selectins and integrins are involved in the metastatic spread of cancer cells. Blocking these interactions has been proposed as a potential strategy to inhibit metastasis [8]. Increased expression of VAMs such as MadCAM-1 in the gut endothelium leads to recruitment of leukocytes to the intestinal mucosa, thereby contributing to the chronic inflammation observed in inflammatory bowel disease. Targeting these adhesion pathways has been found to mitigate inflammation and tissue damage in patients with inflammatory bowel disease [9]. In summary, VAMs have major roles in various diseases and participate in many important pathways (Figure 1).
Vascular adhesion molecules, the biological pathways in which they participate, and their associated cardiovascular diseases.
Abbreviations: MadCAM-1, Mucosal Vascular Addressin Cell Adhesion Molecule-1; ICAMs, Intercellular Adhesion Molecules; PECAM-1, Platelet Endothelial Cell Adhesion Molecule-1.
In recent years, scientists have also explored associations between VAMs and CVDs (Figure 1). VAM levels are crucial mediators of endothelial dysfunction, which is a precursor to the development and acceleration of atherosclerosis. Dysfunctional endothelium exhibits elevated levels of ICAM-1 and VCAM-1, which attract circulating monocytes. These monocytes differentiate into macrophages and consume lipids, thereby forming foam cells and contributing to the development of plaques [10]. The chronic inflammatory state perpetuated by the continual recruitment of leukocytes exacerbates endothelial damage and plaque instability. VAMs are involved in inflammatory processes that lead to plaque instability. High levels of ICAM-1 and VCAM-1 are found in unstable plaques, where they mediate the adhesion of leukocytes, including antigen-presenting cells, such as monocytes and T-cells, to the endothelium. These processes contribute to an inflammatory milieu promoting plaque instability and rupture. Plaque rupture exposes the thrombogenic core to the bloodstream, thus leading to intravascular thrombus formation and potentially myocardial infarction or atherothrombotic stroke [11]. Patients with stable coronary artery disease or acute myocardial infarction show significantly elevated VAMs as part of the inflammatory response. ICAM-1 and VCAM-1 facilitate the infiltration of neutrophils and monocytes into infarcted tissue, and consequently contribute to further myocardial damage and adverse cardiac remodeling [12]. Additionally, in another cohort study, PECAM-1 levels have been found to be associated with coronary artery disease. In that study, a comparison of serum PECAM-1 levels between patients with CAD (n = 137) and controls (n = 110) indicated that higher PECAM-1 levels were associated with lower risk of serious coronary artery stenosis [13]. Elevated serum levels of VAMs such as ICAM-1, VCAM-1, and E-selectin serve as biomarkers for cardiovascular risk assessment. The levels of these biomarkers correlate with atherosclerosis severity and can predict the occurrence of cardiovascular events. Monitoring these biomarkers can aid in early detection and management of CVDs, and can guide therapeutic interventions to reduce risk.
Several therapeutic agents have been developed or are under investigation to target VAMs for the treatment of CVD. The objective of these therapeutic modalities is to decrease the inflammatory response, prevent the adhesion and transmigration of leukocytes, and stabilize atherosclerotic plaques. For instance, natalizumab targets α4-integrin, a protein that interacts with VCAM-1. This finding highlights the potential for similar approaches in treating CVD by preventing leukocyte adhesion to the endothelium [14]. Small molecule inhibitors, such as the statins atorvastatin and simvastatin, decrease not only cholesterol levels but also the expression of VAMs including VCAM-1, ICAM-1, and E-selectin. This anti-inflammatory effect contributes to cardiovascular protective benefits [15]. Furthermore, gene therapy has been widely applied to treat CVDs [16, 17]. For instance, the use of RNA interference to silence VCAM-1 expression in endothelial cells has shown promise in decreasing atherosclerotic plaque formation in preclinical studies [18]. Anti-inflammatory therapy can also be effective in treating CVDs. Canakinumab, an antibody targeting IL-1β, decreases systemic inflammation and subsequently VAM expression. The CANTOS trial has demonstrated the effectiveness of this drug in preventing recurrent cardiovascular events, thereby highlighting the roles of inflammation and VAMs in CVD [19]. Specific dietary components such as omega-3 fatty acids decrease the expression of VAMs, thereby conferring cardiovascular protection. Regular physical activity and a balanced diet can also decrease systemic inflammation and VAM levels. Targeting of VAMs is a promising therapeutic strategy for the management of CVD. Lipid-lowering agents, such as statins and PCSK9 inhibitors are increasing understood to potentially indirectly affect VAM expression. Growing evidence indicates that these agents may effectively prevent major atherothrombotic cardiovascular events. Moreover, emerging therapies, including monoclonal antibodies and gene therapy, offer possibilities of more direct targeting of these adhesion molecules, and may provide new avenues for CVD treatment and prevention.
In conclusion, VAMs appear to play important roles in the development of CVD. The roles of these molecules in mediating inflammation, endothelial dysfunction, and plaque formation suggest that they may be important as both biomarkers and therapeutic targets. Understanding and targeting these molecules are hoped to substantially contribute to improving the prevention and biomarker-guided treatment of CVD.