Michael W Stewart, MD
Among the growth factors and cytokines involved in the pathogenesis of diabetic macular edema (DME), vascular endothelial growth factor (VEGF) accounts for the largest effect, and is both necessary and sufficient to cause leakage. There are 5 subtypes of VEGF, VEGF-A through VEGF-E, but only VEGF-A, which itself has 5 isoforms, has been studied in diabetes. Of the 3 receptors for VEGF, only 1 has been associated with the development of diabetic microvascular complications (DMC): VEGFR-2, which influences vascular permeability, angiogenic, and mitogenic changes. The role of VEGF in DMC is well known, but VEGF may also play a role in the development of diabetic macrovascular complications. Cardiologists worry that VEGF might promote vascularization of the heart. VEGF also causes leukocyte adhesion to cell surfaces.
VEGF is produced within the retina; the retinal pigment epithelium (RPE) plays a key role in its regulation. The RPE and Müller cells are the most important cell types for VEGF production; vascular endothelial cells are the most important VEGF target. Pigment epithelium-derived factor (PEDF) is an anti-VEGF compound. In patients with DME, aqueous VEGF levels are closely correlated with severity of DME.
Hypoxia induces VEGF production, possibly through hypoxia-inducible factor-1 (HIF-1), which has been called the “master switch” for cells. The cell uses an intact mitochondrial electron transport chain and reactive oxygen species (ROS) as oxygen indicators. Iron chelators may create a syndrome that mimics hypoxia.
VEGF production has other important consequences. VEGF production activates protein kinase C (PKC)—a family of signaling enzymes for several growth factors, neurotransmitters, and cytokines—which further increases vascular permeability. Two mechanisms by which PKC increases vascular permeability have been proposed: activation of endothelial cell contraction and dephosphorylation of tight junction proteins. PKC also increases matrix protein accumulation by inhibiting nitrous oxide synthesis. PKC is thought to play a key role in blood-retinal barrier breakdown which can be blocked by PKC inhibitors.
VEGF also has inflammatory effects. It has been noted that patients with concomitant diabetes and rheumatoid arthritis (RA) have much less diabetic retinopathy than patients with diabetes without RA. It has been proposed that the anti-inflammatory medications taken for RA may be responsible for the beneficial effect on diabetic retinopathy.
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