Endothelial Cell Neuropilin

Neuropilin Expression

Cultured EC express both NRP1 and NRP2. However, NRPs are expressed in vivo on specific EC types. For example, it has been demonstrated that there are differential embryonic blood vessel expression patterns for NRP1 and NRP2 in the avian vascular system. In the avian vasculature, NRP1 and NRP2 are both expressed in blood islands, which are the earliest vascular structures. However, once arteries and veins differentiate, NRP1 is expressed in arterial EC and in mesenchyme surrounding developing arteries, whereas NRP2 is expressed only in the venous EC. Similar expression patterns were reported in mice. In the developing mouse skin and retina, NRP1 is predominantly expressed in EC of arteries and arterioles. NRP2 expression was restricted to EC of veins at E10, but from E13 and on, NRP2 was downregulated in veins and highly expressed on lymphatic EC.

Neuropilin-Mediated VEGF Activity in Endothelial Cells

NRP1 appears to be a co-receptor for VEGFR-2 in cultured EC. When co-expressed in cells with VEGFR-2, NRP1 enhances the binding of VEGF165 to VEGFR-2 and VEGF165-mediated chemotaxis as compared to cells expressing VEGFR-2 only. Conversely, inhibition of VEGF165 binding to NRP1 inhibits its binding to VEGFR-2

and its mitogenic activity for EC. VEGF165 binds NRP1 via its exon 7-encoded peptide, whereas it binds VEGFR-2 via its exon 4-encoded peptide. VEGF165 may form a bridge between the two receptors, facilitating a better presentation of VEGF165 to VEGFR-2 (Figure 1). Support for this model was shown in immunoprecipitation studies where NRP1 and VEGFR-2 were co-immunoprecipitated only in the presence of VEGF165. However, other reports have suggested that NRP1 can directly interact with VEGFR-2.

Semaphorin-Mediated Neuropilin Activity in Endothelial Cells

NRPs bind class 3 semaphorins, regulators of neuronal guidance. Semaphorin 3A (Sema3A), which is the best characterized semaphorin, repels axons, collapses dorsal root ganglion neuronal growth cones, and regulates migration of cortical neurons in an NRP 1-dependent manner. These effects are mediated by small GTPases such as Rho A and Rac, which induce actin depolymerization. NRPs do not appear to directly activate signaling pathways in neurons. Instead, signaling is mediated by the interactions of a Sema3A/NRP1 complex with plexins, which are transmembrane signaling receptors. NRP1/plexin complex formation enhances Sema3A binding to NRP1. L1, a neuronal adhesion molecule, has also been demonstrated to be a component of the Sema3A receptor complex (Figure 1).

Sema3A binds EC via NRP1 and inhibits the motility of EC and capillary sprouting from rat aortic ring segments in an in vitro angiogenesis assay. The inhibition of EC motility by Sema3A is competed by VEGF165. VEGF165 and Sema3A are also antagonists in neuronal survival/apoptosis assays. Thus, a balance of semaphorins and VEGF165 can modulate both EC and neuronal activities.

The role of semaphorins in vascular development has been analyzed in several models, and they have been shown to be regulators of vascular development. In chick limb development, overexpression or sequestering of Sema3A abrogated both vascular and neuronal patterning. In addition, it has recently been shown that in the chick embryo, EC express Sema3A, which autoregulates EC motility and vascular morphognesis via NRP1 and Plexin A1 complexes.

In zebrafish, semaphorins regulate the pathway of dor-sally migrating angioblasts, which are NRP 1-positive endothelial precursor cells that migrate to generate the dorsal aorta. Ubiquitous overexpression or knockdown of Sema3a1 protein interrupted dorsal migration of angioblasts and retarded development of the dorsal aorta, resulting in severely diminished blood circulation. Thus, Sema3a1 is a key regulator of early zebrafish vascular development.

In mice, however, transgenic studies seem to indicate that Sema3A does not play a role in regulating the vasculature. An initial report demonstrated that blood vessels developed normally in the limbs of Sema3A knockout mice. Consistent with this observation, transgenic mice overexpressing a

Essentials of Human Physiology

Essentials of Human Physiology

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