Is Angiostatin Involved in Physiological Foveal Avascularity?

Abstract

PURPOSE. The primate central retina is characterized by an avascular fovea and well-defined perifoveal capillary plexus. Neither blood vessels nor their accompanying astrocytes enter the fovea during any stage of retinal development; a balance of angiogenic and angiostatic factors probably maintains foveal avascularity throughout life. The aim of this study was to identify potentially angiorepulsive factors involved in the development of the avascular primate retinal fovea. METHODS.Retinas of newborn, juvenile, and adult Callithrix jacchus and Macaca fascicularis monkeys and control human retinas were studied to determine the localization of angiostatin relative to III b-tubulin, glial fibrillary acidic protein, vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (PECAM), and the angiostatin receptor avb3-integrin in the foveal, macular, and peripheral retina. Expression studies were performed using immunohistochemistry (IHC) on retinal whole-mount and paraffin sections, and Western blotting on frozen material. The complex network of the main retinal cell types was identified by IHC of retinal whole mounts. RESULTS.In general, lifetime expression of angiostatin was found in all retinas. Colabeling with different markers revealed retinal ganglion cells as the main source of angiostatin expression in the primate retina, whereas PECAM-immunopositive blood capillaries expressed the angiostatin receptor avb3-integrin, and capillary-associated astrocytes expressed VEGF.CONCLUSIONS. This study provides the first evidence of angiostatin expression in the primate retina; the expression of angiostatin in the avascular foveal region and the peripheral retina suggests that angiostatin may play a role in the regulation of retinal vascularization, providing a possible explanation for the development and persistence of an avascular fovea.

Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

“…According to the data of [37], MMP-2 and -9 are most frequently synthesized metalloproteinases in astrocytes. In addition, astrocytes express uPAR/uPA-plasminogen activating cascade [10]. It is worth noting that our data are in agreement with the report of Li [38] indicating that human glioma cell line BT325 can convert purified Pg to angiostatin-like fragments with molecular masses of 65, 60, and 58 kDa.…”

“…Currently, numerous reports indicate that various cell types are able to gene rate angiostatins in relatively high amounts [8,9]. In the previous papers, angiostatins are described as constantly formed by several types of retina-resident cells [10]. So far, studies of angiostatins in brain tissue have been limited, with few exceptions [11][12][13], to effects of angiostatin-encoding genetic engineering constructions, which are expressed in the models of rat and human glioma cells developed for testing anti-angiogenic strategy for malignant brain tumor therapy [14,15].…”

“…It is possible that angiostatins regulate functioning of brain capillaries and are involved in maintenance of blood-brain barrier integrity. Recently, it has been obviously demon strated that angiostatins are produced in retina of primates during lifetime and suppress excessive neovascularization of macula, thus maintaining a vascular retinal fovea [10]. The potential pathophysiological significance of these proteins may further attract much attention thanks to the recent observations that spectrum of effects, including reducing inflammatory reactivity, stabilization of vascular remodeling and neuroprotection.…”

“…It is known that as a result of damage to neural tissue, ishemic condition, or some metabolic disorders astrocytes acquire reactive phenotype and display pro-angiogenic activity, probably reflec ting compensatory mechanisms [18]. In the healthy retina, astrocytes constanlty release antiangiogenic factors through exocytosis that counteract VEGF-angiogenic stimuli and prevent neovascularization surplus, formation of leaky cappilaries with abnormal structure [10,36]. Therefore, the similar event may take place in cerebral cortex, and angiostatins may be involved in regulation of microvasculature behavior in cortical networks and influence microangiogenesis.…”

Immunohistological Study of Monkey Foveal Retina

“…Böhm et al . reported that the foveola in humans and in rhesus monkeys displayed immunostaining for Tuj-1 49 . Tuj-1-positive cells in this area are probably ganglion cells, or their precursor.…”