Association of Retinopathy and Retinal Microvascular Abnormalities With Stroke and Cerebrovascular Disease.

BACKGROUND AND PURPOSE: Abnormalities of the retinal circulation may be associated with cerebrovascular disease. We investigated associations between retinal microvascular abnormalities and (1) strokes and subclinical cerebral infarcts and (2) cerebral white matter lesions in a UK-based triethnic population-based cohort. METHODS: A total of 1185 participants (age, 68.8±6.1 years; 77% men) underwent retinal imaging and cerebral magnetic resonance imaging. Cerebral infarcts and white matter hyperintensities were identified on magnetic resonance imaging, retinopathy was graded, and retinal vessels were measured. RESULTS: Higher retinopathy grade (odds ratio [OR], 1.40 [95% confidence interval (95% CI), 1.16-1.70]), narrower arteriolar diameter (OR, 0.98 [95% CI, 0.97-0.99]), fewer symmetrical arteriolar bifurcations (OR, 0.84 [95% CI, 0.75-0.95]), higher arteriolar optimality deviation (OR, 1.16 [95% CI, 1.00-1.34]), and more tortuous venules (OR, 1.20 [95% CI, 1.09-1.32]) were associated with strokes/infarcts and white matter hyperintensities. Associations with quantitative retinal microvascular measures were independent of retinopathy. CONCLUSIONS: Abnormalities of the retinal microvasculature are independently associated with stroke, cerebral infarcts, and white matter lesions.

Impact of fetal growth and preterm birth on the retinal microvasculature in mid-adulthood.

OBJECTIVE: We hypothesized that preterm birth and being born SGA would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We further hypothesized that these microvascular changes would correlate with early markers of CVD in mid-adulthood. METHODS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm, born at term and SGA and a control group born at term and AGA were compared (aged 34-49 years). RESULTS: In participants born preterm, arteriolar tortuosity (×10(2)) was higher-means (standard error), 0.06 (0.01) versus 0.04 (0.01), p = 0.001, arteriolar length (pixels) were greater-644.9 (35.9) versus 591.7 (33.5), p = 0.007 and arteriolar diameters (pixels) were narrower-19.9 (0.4) versus 20.3 (0.3), p = 0.034 compared to participants born AGA, after adjustment. In participants born SGA, only arteriolar tortuosity was higher-0.05 (0.01) versus 0.04 (0.01), p = 0.074 compared to participants born AGA. CONCLUSION: This study demonstrated that being born SGA and in particular preterm birth are associated with changes in retinal microvascular architecture. The prenatal and immediate postnatal environment may contribute to the mechanisms.

Impaired recovery of intracellular calcium and force after activation in isolated myometrial and subcutaneous resistance arteries from women with preeclampsia.

OBJECTIVES: Preeclampsia is a major cause of maternal and perinatal morbidity and mortality, but its cause is poorly understood. This study investigated whether there is an abnormality of intracellular calcium ([Ca2=]i) and tension during recovery from activation in isolated resistance arteries in preeclampsia and investigated the underlying mechanisms. METHODS: Subcutaneous and myometrial resistance arteries from preeclamptic, normotensive pregnant and nonpregnant women were mounted on an isometric myograph and loaded with fura-2 to allow simultaneous measurement of force and [Ca2+]i. Arteries were activated by a high-potassium solution or noradrenaline, and the rate of decline in force and [Ca2+]i examined following washout. RESULTS: Basal tone and [Ca2+]i and rise in force and [Ca2+]i induced by high-potassium solution did not differ between groups but the rate of decline after washout was significantly slowed in both subcutaneous and myometrial arteries from preeclamptic women as compared with normotensive pregnant or nonpregnant women. The rate of decline in force after noradrenaline was also slowed in arteries from preeclamptic women. In subcutaneous resistance arteries from nonpregnant women, removal of the endothelium did not affect the rate of decline in force after high-potassium solution. However, inhibition of the plasma membrane Ca ATPase with carboxyeosin mimicked the findings seen in preeclampsia. In contrast, inhibition of the sarcoplasmic endoreticulum Ca ATPase with cyclopiazonic acid had no effect on the rate of decline in force or [Ca2+]i. CONCLUSION: The rate of relaxation and decline in [Ca2+]i in resistance arteries are impaired in preeclampsia. This may be mediated by decreased activity of plasma membrane Ca2+ ATPase and could be a mechanism contributing to elevated peripheral resistance and raised blood pressure in preeclampsia.

Src family tyrosine kinases mediate contraction of rat isolated tail arteries in response to a hyposmotic stimulus.

OBJECTIVE: Hypotonic solutions cause vasoconstriction in rat tail arteries, due largely to activation of L-type calcium channels (CaV1.2). We studied possible roles of tyrosine kinases, particularly src family kinases (SFK) and extracellular signal-related kinases (ERK1/2), in this response. METHODS: Rat tail arteries were mounted on a myograph for measurement of isometric force. Arteries were bathed in isosmotic physiological saline solution (300 mOsm/l) containing 50 mmol/l mannitol and were stimulated by a hyposmotic solution containing 0 mmol/l mannitol (PSS-M). Activation of tyrosine kinases and ERK1/2 by hyposmotic solution was examined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blotting on rat tail artery lysates with specific phospho-antibodies. RESULTS: Western blotting showed SFK src and yes present in rat tail artery. PSS-M increased tyrosine phosphorylation of several proteins, including SFK and ERK1/2. Genistein blocked phosphorylation of SFK and ERK1/2 by PSS-M. In isolated arteries PSS-M caused a contraction inhibited by the tyrosine kinase inhibitor, genistein, and three structurally different selective SFK inhibitors, herbimycin-A, PP1 and SU6656. Mitogen-activated protein kinase kinase inhibitor PD98059 or selective inhibitors of platelet-derived growth factor receptor (AG1296) and epidermal growth factor receptor (AG1478) had no effect on contraction induced by a hypotonic solution. CONCLUSIONS: Hyposmotic conditions activate SFK, src and yes, and contract rat tail artery by a SFK-dependent mechanism. ERK1/2 are activated by the hypotonic solution, but do not play a role in the contractile response. SFK modulation of CaV1.2 may be an important mechanism mediating vasoconstriction to mechanical stimuli in vascular smooth muscle.

Inhibition of Src family tyrosine kinases prevents lipopolysaccharide-induced hyporeactivity in isolated rat tail arteries.

Tyrosine kinases may play a role in the vascular response to sepsis. We investigated the effect of selective inhibitors of Src family tyrosine kinases (SFK) on lipopolysaccharide (LPS)-induced vascular hyporeactivity. Rat tail artery segments were mounted in an isometric wire myograph. The effect of incubation with LPS was examined on phenylephrine (PE) and high potassium (KPSS)-induced contraction, with and without the selective SFK inhibitors SU6656 or PP1. Western blotting was performed to assess SFK phosphorylation and iNOS induction. Incubation with LPS for 18 h induced marked vascular hyporeactivity to both PE (p<0.001) and KPSS (P<0.001). Incubation with SU6656 alone had no effect on contractility to PE and KPSS, and SU6656 partially prevented LPS-induced hyporeactivity to PE (p<0.01) and KPSS (p<0.001). In contrast, PP1 alone diminished contractility to PE (p<0.01) and KPSS (p<0.001), and co-incubation of LPS with PP1 completely prevented LPS-induced hyporeactivity. LPS increased tyrosine phosphorylation of SFK and this effect was inhibited by SFK inhibitors. LPS also increased levels of iNOS and this was also inhibited by SU6656 and PP1. LPS-induced hyporeactivity in vitro is mediated by activation of SFK. Selective inhibitors of SFK may have therapeutic potential in the management of septic shock.