Wellman et al. 73 endothelial and perivascular cells of the leptomeninges of both control and SWS samples (Figure 2, panels C and D, respectively, and inserts showing blood vessels), while distinct Gαq expression was noted in non-vascular cells of the cortex (Figure 2, panels C and D, corner inserts) and subcortex (data not shown) of both. Comati et al. reported in 20078 that the majority of SWS leptomeninges were thin-walled vessels of variable caliber, ectatic, CD34 labeled, and covered by a layer of smooth muscle/pericytes. They further noted that the abnormal leptomeningeal vessels did not have an internal elastic lamina, indicating that the vessel had venous characteristics. These SWS leptomeningeal endothelial cells had increased expression of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, hypoxia-inducible factor (HIF) 1α and HIF2α. The authors suggested that VEGF released by the underlying hypoxic cortical cells may stimulate increased release of HIF1α by the abnormal leptomeningeal endothelial cells and further increases in VEGF expression. VEGF and VEGFR signal through Gαq, and therefore the hyperactivating R183Q mutation, may increase the expression of HIF1α through the Ras-Raf-MEK-ERK pathway, as suggested by our data. Constitutive hyperactivation of Gαq activity with mutant GNAQ does not necessarily impact levels of the expressed protein itself. Chronic hyperactivation of Gαq activity, due to decreased auto-hydrolysis of GTP to GDP, is predicted to result from the R183Q mutation, which impacts the auto-hydrolysis site. Compensatory changes in gene expression, in response to chronic constitutive activation of Gαq, might even lead to decreased Gαq protein levels, which would not be well measured by this approach (given the already low expression levels in control vessels). Further studies are needed of the Ras-Raf-MEK-ERK pathway to understand the mechanism of ERK hyperactivation by the mutant Gαq protein in SWS. In port-wine birthmarks, increased endothelial p-ERK expression has been reported and may contribute to vascular structural and functional abnormalities. 9 Adult, hypertrophied port-wine birthmarks also demonstrate increased expression of other downstream kinases, suggesting that progressive hyperactivation of such pathways may contribute to worsening vascular ectasis over time. Increased VEGF may contribute to vascular hypertrophy in port-wine birthmarks. 10 We hypothesize that abnormal activation of these pathways results in abnormal gene expression, aberrant endothelial shape and CD34+ expression with breakdown of the endothelial barrier, and abnormal vascular remodeling leading to worsening perfusion deficits and neurologic dysfunction. CD34+ is normally found on small vessels and is lacking on larger vasculature; further study is needed to understand the relationship between decreased CD34+ endothelial expression and dilated leptomeningeal vessels. CD34+ endothelial cells are usually quiescent and are thought to be involved in blocking the migration and