Background-Tetrahydrobiopterin (BH 4 ) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH 4 levels are altered in human atherosclerosis and the importance of BH 4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH 4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. Methods and Results-Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor N G -nitro-L-arginine methyl ester. High vascular BH 4 was associated with greater vasorelaxations to acetylcholine (PϽ0.05), whereas high plasma BH 4 was associated with lower vasorelaxations in response to acetylcholine (PϽ0.05). Furthermore, an inverse association was observed between plasma and vascular biopterins (PϽ0.05 for both saphenous veins and internal mammary arteries). High vascular (but not plasma) BH 4 was associated with reduced total and N G -nitro-L-arginine methyl ester-inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels (PϽ0.001). Conclusions-An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH 4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

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Abstract-Offspring born to mothers with hypertensive pregnancy have higher childhood blood pressure. We hypothesized this relates to prenatally programmed differences in the underlying vascular pathophysiology of the offspring and that these would be most apparent in those born preterm because of severe hypertension. We carried out a 20-year follow-up study of 71 subjects born preterm, 19 to a hypertensive pregnancy and 52 to a normotensive pregnancy. Findings were compared with 38 subjects born at term to uncomplicated pregnancies. Peripheral and central blood pressures were measured, and then central arterial stiffness was assessed by carotid-femoral pulse wave velocity using applanation tonometry. Ultrasound was used to assess flow-mediated endothelial-dependent and independent brachial artery responses and common carotid artery intima-media thickness. Key Words: blood pressure Ⅲ preeclampsia Ⅲ endothelial function Ⅲ fetal programming Ⅲ prematurity D e novo onset hypertension affects 5% to 7% of all pregnancies 1 and is manifest as a spectrum of hypertensive complications ranging from gestational hypertension to severe preeclampsia. 2 Hypertensive pregnancy has 3,4 emerged as an independent risk factor for premature maternal cardiovascular disease, 1,5,6 and recently offspring of hypertensive pregnancies have also been found to be at greater risk of higher blood pressure in childhood 7-11 and stroke in later life. 12 Furthermore, the risk to the offspring is graded and greatest in those whose mothers had more severe hypertensive signs, such as early onset hypertension or preeclampsia. 12 Severe hypertensive pregnancy is commonly associated with premature delivery and intrauterine growth restriction. 13 Prematurity and growth restriction, in turn, have been independently linked with hypertension and cardiovascular complications in the offspring, 14 -16 and it is postulated that this is mediated through intrauterine conditions adversely affecting the development of the offspring vascular system. 17 Interestingly, despite both prematurity and intrauterine growth restriction leading to the same clinical sequelae of hypertension, the persistent underlying vascular phenotype appears to vary with, for example, only the term intrauterine growthrestricted offspring exhibiting endothelial dysfunction. 15,18 -20 Better understanding of the long-term changes in vascular pathophysiology related to different pregnancy complications may allow novel primary cardiovascular prevention strategies targeted at key aspects of vascular function. 21

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