Vascular changes in the subventricular zone after distal cortical lesions

Abstract

One of the effects of cortical lesions is to produce cell proliferation in the subventricular zone (SVZ), a neurogenic zone of the adult brain distal from the lesion. The mechanisms of these effects are unknown. Recent evidence points to a relationship between the vasculature and neurogenesis both in vitro and in vivo. In the present study, we asked whether cortical lesions induced vascular modifications in the distal SVZ in vivo. Lesions of the frontoparietal cortex were produced by thermocoagulation of pial blood vessels, a method that leads to highly reproducible loss of all cortical layers, sparing the corpus callosum and underlying striatum. These lesions induced increased immunoreactivity for vascular endothelial growth factor (VEGF) around the walls of SVZ vessels, at a considerable distance from the lesion. Vascular permeability was markedly increased in both the SVZ and RMS by 3 days after the injury. A dramatic increase in endothelial proliferation was followed by expansion of the local SVZ vascular tree 7 days after the injury. This time course corresponded to the proliferative changes in the SVZ, and a tight correlation was observed between the number of blood vessels and the increase in SVZ cell number. The data demonstrate that thermocoagulatory cortical lesions induce distal vascular changes that could play a role in lesion-induced SVZ expansion.

Introduction

The subventricular zone (SVZ) of the adult brain contains rapidly dividing cells that either die in place or migrate several millimeters through the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into neurons in the granule and periglomerular layers (Lois and Alvarez-Buylla, 1994, Morshead and van der Kooy, 1992). This suggests that SVZ cell number is controlled by balancing cell proliferation with cell death and rostral migration. This balance, however, can be disrupted by brain injury. Szele and Chesselet (1996) reported that aspiration lesions of the cerebral cortex resulted in increased cell number in the SVZ. More recently, bromodeoxyuridine (BrdU) incorporation in the SVZ has been shown to increase following large corticostriatal ischemic injuries (Jin et al., 2001, Parent et al., 2002b), global ischemia (Tonchev et al., 2003), trauma (Chirumamilla et al., 2002), and status epilepticus (Parent et al., 2002a). We have shown that, after ischemic lesions restricted to the cerebral cortex, increased cell proliferation precedes a marked increase in SVZ cell number, and neuroblasts migrate in the striatum and corpus callosum without disruption of neurogenesis in the olfactory bulb (Gotts and Chesselet, in press-a, Gotts and Chesselet, in press-b).

The mechanisms triggering these alterations in the normally tight control over cell number in the SVZ are unknown. In normal brain, a close association exists between neurogenesis and angiogenesis both in neurogenic zones of the hippocampus (Palmer et al., 2000) and songbird HVC (Louissaint et al., 2002). Furthermore, factors released by endothelial cells in vitro trigger neural stem cell proliferation (Shen et al., 2004). It is unknown, however, whether distal cortical lesions that cause expansion of the SVZ in adults induce vascular changes in the SVZ. Such changes could point to a similar association between angiogenesis and cell proliferation after injury.

We have examined vascular changes induced in the SVZ shortly after lesion of the frontoparietal cortex in adult rats. Lesions were induced by thermocoagulation of pial blood vessels (Errami and Nieoullon, 1986, Salin et al., 1990). With this method, cell loss resulting from ischemic and limited thermal injury includes all cortical layers and is both extremely reproducible and confined to the cerebral cortex, which presents a distinct advantage over other types of ischemic lesions. This model has been extensively characterized in terms of molecular effects, behavior, electrophysiological consequences, and patterns of axonal and synaptic loss and plasticity (Carmichael and Chesselet, 2002, Napieralski et al., 1996, Napieralski et al., 1998, Salin and Chesselet, 1992, Salin and Chesselet, 1993, Szele et al., 1995, Uryu et al., 2001). Notably, these lesions spare the corpus callosum and do not induce neuronal loss in the striatum (Carmichael and Chesselet, 2002, Salin and Chesselet, 1992, Szele et al., 1995). Immunohistochemical changes indicative of cellular stress are limited to the ipsilateral cerebral cortex surrounding the lesion (Szele et al., 1995). However, these cortical lesions induce a massive increase in cell number in the SVZ, at a considerable distance from the injury (Gotts and Chesselet, in press-a), an effect similar to that observed after similarly located cortical lesions induced by aspiration (Szele and Chesselet, 1996).

To identify lesion-induced disturbances that could affect the SVZ and RMS, we examined changes in the vasculature of these regions. We show a succession of increased vascular endothelial growth factor (VEGF), increased vascular permeability, and the formation of new blood vessels in these neurogenic zones, with a time course compatible with a role in SVZ cell proliferation and expansion.