Possible mechanisms by which neuroglial cells communicate with vascular cells have been investigated. Some of these signaling molecules act rapidly (such as H⁺, K⁺, neurotransmitters, adenosine, arachidonic acid metabolites, and nitric oxide [NO]), whereas others seem to have a more prolonged effect (such as growth factors) [4,12,13]. It seems clear that the control of microcirculation by neuroglia is a complex process that likely involves a number of different molecules [14]. Some of these molecules are listed here.

1) NO can be made by every retinal cell type, and it is an important signaling molecule that regulates neurotransmitters release and modulates gap junction conductivity in retina. In the retina, the NO produced by the constitutive nitric oxide synthases (NOSs; endothelial NOS and neuronal NOS) contribute to regulate normal ocular hemodynamics and cell viability, and to protect retinal cells against different stresses [15,16]. Pretreatment of animals with a NO inhibitor inhibited the flicker-induced increase in retinal blood flow [17], indicating that NO plays an important role in the coupling between retinal neuronal activity and blood flow.

2) Metea and Newman [18] demonstrated that retinal glial cells mediate neurovascular coupling by inducing the production of two arachidonic acid metabolites, epoxyeicosatrienoic acids, and 20-hydroxyeicosatetraenoic acid, which dilate and constrict vessels, respectively. They showed that 1) light or direct glial stimulation produce vasodilatation or vasoconstriction mediated by these small molecules, 2) the vascular response depends on NO, and 3) glial cells are necessary for signaling from neurons to blood vessels.

3) Studies have demonstrated that a large fraction of neurovascular coupling that causes hyperemia is due to release of glutamate from neural tissue [19].

4) Vascular endothelial growth factor (VEGF) is another soluble factor that couples neuroglia and the vasculature. VEGF is produced largely by glia and neurons. It is known to have important effects on vascular development, permeability and, in ischemic diseases, also neovascularization [20].

5) Neurotrophins are another way by which neural tissue might communicate with the retinal vasculature. The neurotrophins are a family of trophic factors (including nerve growth factor [NGF], brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5) which promote neural cell survival, neurite outgrowth, phenotypic maturation, and synaptic functioning, but also exert a trophic effect on some, but perhaps not all, endothelial cells. Endothelial cells from the brain, dermis, and umbilical vein have been reported to contain the NGF receptors TrkA and p75NGFR, and to respond to NGF with cell mitosis, migration, and survival. Cerebral endothelial cells, however, have been reported to not respond to NGF [21].

Whereas a variety of studies describe the effects of flickering light on retinal and optic nerve head blood flow under normal conditions, the knowledge about this coupling in the diabetic retina is less complete. Nevertheless, available evidence indicates that neurovascular coupling in the retina is altered in diabetes. Luu et al. [22] demonstrated that a component of the neural oscillatory potential of the electroretinogram (ERG) correlated with retinal arteriolar caliber in patients with diabetes, demonstrating at least a correlation between retinal neuronal dysfunction and blood flow. Flicker responses of retinal arteries and veins in insulin-dependent diabetic patients [23] and in healthy subjects made experimentally hyperglycemic [24] have shown significant reduction compared to controls. The flicker-induced retinal diameter change has been shown to deteriorate early in patients with diabetes; Lecleire-Collet et al. [25] found a significant reduction of the flicker-induced response in the retinal arteries and veins of normotensive patients with diabetes with no clinically detectable diabetic retinopathy. Nguyen et al. [26] showed that reduced retinal vasodilation after flicker light stimulation was associated with diabetes, independent of major risk factors such as hypertension and glycemic control. Whether or not there is a difference between type 1 diabetes and type 2 is not clear; a controlled study demonstrated decreases in both arterial and venous flicker-induced retinal vasodilation in normotensive patients with type 1 diabetes and no diabetic retinopathy [27], whereas an uncontrolled study of patients with type 2 diabetes by the same research group [28] demonstrated that the observed decreases in the arterial and venous flicker-induced responses were no longer significant after factoring out age and antihypertensive treatment.

The impaired flicker-induced vascular response may be partly caused by endothelial dysfunction, as suggested by Mandecka et al. [27,28] and Nguyen et al. [26,29]. A key role for NO has been identified in retinal and optic nerve vasodilatory response to greater neuronal activity. Light-evoked arteriole dilation (functional hyperemia) is reduced diabetic rats, and inhibition of iNOS restored both light- and glial-evoked dilation of retinal arterioles to control levels [30].

Diabetic retinopathy is a common complication of diabetes and a leading cause of legal blindness among working-age adults. Historically, diabetic retinopathy researchers and physicians have concentrated on the vascular lesions in this disease, since those are what seem to account for most of the lesions that contribute to vision loss in diabetes. It is now clear that the neuronal components of the retina are also injured in diabetes, and appear to become impaired prior to the regression of the retinal vasculature. We will first present a brief summary of diabetic retinopathy, and then summarize recent evidence that neural abnormalities within the retina are actually contributing to the vascular lesions of the retinopathy.