Deletion of Sema4D gene reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice

Abstract

Abstract. Neovascularization occurring in atherosclerotic plaque leads to acceleration of plaque growth through increased leukocyte infiltration and reactive oxygen species (ROS) production. Sema4D (CD100), a class IV semaphorin, not only plays a crucial role in axon guidance but also functions in the neovascularization process of tumor growth. To clarify the roles of Sema4D in the progression of atherosclerosis and neovascularization of atherosclerotic plaque, we analyzed the effect of Sema4D gene deletion from apolipoprotein E (ApoE)-deficient mice in the development of atherosclerosis. Lipid staining demonstrated significant decreases in plaque areas in the aortas of 6-month-old Sema4D -/-ApoE -/-mice compared with 6-month-old ApoE -/-mice. Thus, the Sema4D gene knockout in ApoE-deficient mice was found to slow the progression of atherosclerosis. Immunohistochemical analyses confirmed the expression of Sema4D protein in infiltrating lymphoid cells in atherosclerotic plaque and plexin-B1 receptor in neovascular endothelial cells within the plaque. Furthermore, there were significant decreases in the degree of neovascularization in the plaque areas of Sema4D -/-ApoE -/-mice compared with ApoE -/-mice as revealed by both isolectin B4 and CD31 staining. The number of infiltrating macrophages in Sema4D -/-ApoE -/-mice plaques was also significantly less than those in ApoE -/-mice. These findings suggest that Sema4D is involved in the progression phase of atherosclerosis by accelerating intimal neovascularization, resulting in enhanced macrophage infiltration in atherosclerotic plaques.

Semaphorin Signaling in Cardiovascular Development

“…For example, Sema4a binds to Plxnd1 and inhibits developmental angiogenesis (Toyofuku et al, 2007), and Sema4d signals via Plxnb1 on endothelial cells to regulate motility (Yukawa et al, 2010). Sema5a signals through the receptor Plxnb3 (Artigiani et al, 2004), and mice lacking Sema5a show defective remodeling of cranial blood vessels.…”

“…Sema4d promotes angiogenesis Yukawa et al, 2010;Zhu et al, 2009. Sema6d À/À Plexin A1 Viable No obvious phenotype in mice.…”

Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets

“…21,22 In previously published studies, we have shown that Sema4D is expressed by platelets and that it participates in the hemostatic response to injury by reinforcing collagen-initiated platelet activation in a contact-dependent manner. 23,24 Deletion of Sema4D protects mice against the development of atherosclerosis by attenuating platelet hyperactivity in the setting of hyperlipidemia 25 and reducing intimal neovascularization, 26 which suggests that platelet Sema4D has an impact on the vessel wall as well as on platelets. Our previous studies also showed that the extracellular domain of Sema4D is gradually shed from the surface of activated platelets as a soluble 120-kDa fragment that retains biological activity.…”

Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone

“…By contrast, neither ␤-gal nor Plexin-B2 were detected in GFAP-positive astrocytes that ensheath migrating neuroblasts. We next studied the expression pattern, in the forebrain of P8 mice, of the four class IV semaphorins that were previously shown to bind Plexin-B2 namely Sema4A, Sema4C, Sema4D, and Sema4G (Oinuma et al, 2004;Deng et al, 2007;Yukawa et al, 2010b;Maier et al, 2011;Perälä et al, 2011). This showed that Sema4C, 4D, and 4G are all expressed in the RMS and in the GCL (Fig.…”