*Review* **Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System**

**Silvia Silva-Hucha, Angel M. Pastor and Sara Morcuende \***

Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, 41012 Sevilla, Spain; silvia\_sh88@hotmail.com (S.S.-H.); ampastor@us.es (A.M.P.)

**\*** Correspondence: smorcuende@us.es; Tel.: +34-954-55-95-49

**Abstract:** Vascular endothelial growth factor (VEGF) was initially characterized as a potent angiogenic factor based on its activity on the vascular system. However, it is now well established that VEGF also plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons. These motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem pools. That higher VEGF level could be due to an enhanced retrograde input from their target muscles, but it can also be produced by the motoneurons themselves and act in an autocrine way. By contrast, VEGF's paracrine supply from the vicinity cells, such as glial cells, seems to represent a minor source of VEGF for brainstem motoneurons. In addition, ocular motoneurons experiment an increase in VEGF and Flk-1 level in response to axotomy, not observed in facial or hypoglossal motoneurons. Therefore, in this review, we summarize the differences in VEGF availability that could contribute to the higher resistance of extraocular motoneurons to injury and neurodegenerative diseases.

**Keywords:** VEGF; oculomotor system; trophic factors; motoneurons; neurodegeneration; axotomy; amyotrophic lateral sclerosis

**1. Vascular Endothelial Growth Factor (VEGF)**

*1.1. History*

VEGF was initially described as an angiogenic factor and, consequently, it was named vascular permeability factor (VPF) for its role in inducing vascular permeability in tumor cells [1]. It was not until 1989 when the VEGF protein, whose molecular weight is approximately 45 kDa, was purified and sequenced, and it was definitively assigned the name of vascular endothelial growth factor [2,3].

It is well known that this factor is a highly specific mitogen for vascular endothelial cells, whose family consists of multiple cell signaling proteins involved in angiogenesis, lymphangiogenesis, vasodilation, and vascular leakage, among other functions [4]. In 2001, his essential role in motoneuronal protection was revealed for the first time [5], as will be discussed later in detail.
