Neuronal guidance proteins in cardiovascular inflammation

Abstract

Cardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

Keywords: Atherosclerosis; Cardiovascular inflammation; Myocardial infarction; Neuronal guidance proteins.

Fig. 1

Overview of neuronal guidance protein family members with relevance in the cardiovascular system. Schematic drawing of the expression of NGP in specific tissues and sites of action (ligands in the left columns and receptors in the right columns; with Eph ephrin receptors, Ntn netrin, Plx plexin, Sema semaphorin)

Fig. 2

Role of NGPs in the development of atherosclerosis. Sema3A expression is decreased in the stressed endothelium, Sema3A overexpression successfully inhibits VSMC proliferation and migration; Sema3A also inhibits monocyte adhesion and migration. Sema4D and its receptor PlxB1 promote monocyte adhesion to the endothelium, impair platelet aggregation and regulate the atherosclerotic lesion size. Sema7A regulates the expression of ICAM-1, VCAM-1 and P-selectin on the endothelial surface, promoting leucocyte adhesion and plaque formation. Sema7A also modulates intraplaque neovascularization via β1 integrin-dependent induction of VEGFA/VEGFR expression in endothelial cells. Ntn1 regulates the adhesion molecules VCAM-1, ICAM-1 and E-selectin and prevents macrophages from emigrating from plaques. Ntn1 further inhibits the migration of VSMCs into lesions. Ephrin-A1, Ephrin-B1 and Ephrin-B2 regulate the migration of monocytes into the vascular wall (with Ntn netrin, Plx plexin, Sema semaphorin)

Fig. 3

Role of NGPs in inflammation during myocardial ischaemia–reperfusion injury. Sema3A expression is induced by AMI, dampens the inflammatory response and decreases infarct size. Sema4D levels are elevated in patients presenting with acute coronary syndrome, reflecting the inflammatory component of myocardial ischaemia. Sema7A activates the platelet GPIb receptor during IR injury, resulting in the formation of platelet–neutrophil complexes and the aggravation of tissue injury. Neuropilin-1 improves electrical remodelling at the infarct border, reduces infarct sizes and functions as a VEGFB receptor, promoting angiogenesis, anti-apoptotic and cardioprotective metabolic shifts in the ischaemic myocardium. Ntn1 substantially reduces the infarct size through NO and the recruitment of pro-resolutionary macrophages. Ephrin-A1 expression is decreased following myocardial infarction in mice, and exogenous ephrin-A1 dramatically diminishes tissue injury and leads to functional improvement. (with Ntn netrin, NO nitric oxide, Plx plexin, Sema semaphorin)

Fig. 4

Interaction between platelets and NGPs. a Sema7A influences megakaryopoiesis and reduces differentiation and megakaryocyte and platelet production. It also interacts with the platelet GPIb receptor and activates platelets through this receptor. b PlxB2 functions as a receptor for Sema4C and regulates the activation and thrombotic activity of platelets. c Sema3A interacts with PlxA1-3 and inhibits the secretion of granules and aggregation of platelets. d Sema4D phosphorylates glycoprotein VI and Syk as downstream targets of Clec-2. e Slit-2 was shown to inhibit platelet adhesion, aggregation and granule secretion via the Robo-1 receptor (with Sema Semaphorin, Plx Plexin)