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Background: White matter hyperintensities (WMHs) are a risk factor for stroke. Their etiology is considered to be cerebral microvascular abnormality. However, the association between WMHs and arteriosclerosis is not yet clear. The aim of this hospital-based cohort study was to identify the arteriosclerotic characteristics associated with WMHs. Methods: We cross-sectionally included 240 consecutive patients with no history of stroke. We measured the brachial-ankle pulse wave velocity (baPWV), ankle brachial pressure index, and intima-media thickness of the common carotid artery, and we performed magnetic resonance brain imaging. WMHs were defined as periventricular hyperintensity (Fazekas grade ≧3) and/or separate deep white matter hyperintense signals (Fazekas grade ≧2). We determined the prevalence of WMHs, silent brain infarction (SBI), hypertension, hypercholesterolemia, diabetes mellitus, ischemic heart disease, and smoking. We compared 2 groups of patients, defined by the presence or absence of WMHs, using multiple logistic regression analyses. Results: In multivariable analysis, SBI (OR 3.38; 95% CI 1.52–7.72), hypertension (OR 2.23; 95% CI 1.03–5.15), female sex (OR 1.95; 95% CI 1.03–3.76), baPWV (OR 1.12; 95% CI 1.02–1.23), and age (OR 1.09; 95% CI 1.04–1.14) were independently associated with WMHs. Conclusions: An increased baPWV is associated with WMHs. Management of increased baPWV may help to prevent the progression of WMHs and stroke.

Phospholipase C is a novel class of phosphoinositide-specific phospholipase C, identified as a downstream effector of Ras and Rap small GTPases. We report here the first genetic analysis of its physiological function with mice whose phospholipase C is catalytically inactivated by gene targeting. The hearts of mice homozygous for the targeted allele develop congenital malformations of both the aortic and pulmonary valves, which cause a moderate to severe degree of regurgitation with mild stenosis and result in ventricular dilation. The malformation involves marked thickening of the valve leaflets, which seems to be caused by a defect in valve remodeling at the late stages of semilunar valvulogenesis. This phenotype has a remarkable resemblance to that of mice carrying an attenuated epidermal growth factor receptor or deficient in heparin-binding epidermal growth factor-like growth factor. Smad1/5/8, which is implicated in proliferation of the valve cells downstream of bone morphogenetic protein, shows aberrant activation at the margin of the developing semilunar valve tissues in embryos deficient in phospholipase C. These results suggest a crucial role of phospholipase C downstream of the epidermal growth factor receptor in controlling semilunar valvulogenesis through inhibition of bone morphogenetic protein signaling.The hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) by phosphoinositide-specific phospholipase C (PLC) is a key event triggering intracellular signal transduction from various receptor molecules at the plasma membrane by yielding two intracellular second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which induce activation of protein kinase C and mobilization of Ca 2ϩ from intracellular stores, respectively (9). Concurrently, reduction in PIP 2 concentration appears to be an important signal because activities of various actin-binding proteins and pleckstrin homology domain-containing proteins are modulated through interaction with PIP 2 (25). More than 12 mammalian PLC isoforms have been identified and organized into five classes (␤, ␥, ␦, ε, and ), which are regulated through distinct mechanisms (9). PLCε is characterized by possession of two Ras-associating domains and a CDC25 homology domain. The Ras-associating domains are responsible for activation of PLCε through direct association with the GTP-bound active forms of the small GTPases Ras (15, 23), Rap1 (23,24), and Rap2 (20). Stimulation of cells by growth factors, such as platelet-derived growth factor, induces persistent activation of PLCε through activation of Ras and Rap1 (24). The rapid and initial phase of this activation is mediated by Ras at the plasma membrane, whereas Rap1 is responsible for the prolonged activation mainly at the Golgi complex (24). The CDC25 homology domain acts as a guanine nucleotide exchange factor for Rap1 and is crucial for the prolonged activation of PLCε by Rap1 (14,24). The involvement of other factors, such as the ␣ subunits of the G 12 and G 13 families or the ␤ 1 ␥ 2 subunits ...

Phospholipase C is a key enzyme of intracellular signal transduction in the central nervous system. We and others recently discovered a novel class of phospholipase C, phospholipase Cepsilon, which is regulated by Ras and Rap small GTPases. As a first step toward analysis of its function, we have examined the spatial and temporal expression patterns of phospholipase Cepsilon during mouse development by in situ hybridization and immunohistochemistry. Around embryonic day 10.5, abundant expression of phospholipase Cepsilon is observed specifically in the outermost layer of the neural tube. On embryonic day 12 and later, it is observed mainly in the marginal zone of developing brain and spinal cord as well as in other regions undergoing neuronal differentiation, such as the retina and olfactory epithelium. The phospholipase Cepsilon-expressing cells almost invariably express microtubule-associated protein 2, but hardly express nestin or glial fibrillary acidic protein, indicating that the expression of phospholipase Cepsilon is induced specifically in cells committed to the neuronal lineage. The expression of phospholipase Cepsilon persists in the terminally differentiated neurons and exhibits no regional specificity. Further, an in vitro culture system of neuroepithelial stem cells is employed to show that abundant expression of phospholipase Cepsilon occurs in parallel with the loss of nestin expression as well as with the induction of microtubule-associated protein 2 expression and neuronal morphology. Also, glial fibrillary acidic protein-positive glial lineage cells do not exhibit the high phospholipase Cepsilon expression. These results suggest that the induction of phospholipase Cepsilon expression may be a specific event associated with the commitment of the neural precursor cells to the neuronal lineage.

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