Background-Clinical and experimental evidence suggest that the adventitia participates in the response to endoluminal vascular injury. The current study used a direct approach to test the hypothesis that, after balloon injury of the rat carotid artery, adventitial fibroblasts migrate in a luminal direction and contribute to neointima formation. Methods and Results-Primary syngeneic adventitial fibroblasts were stably transduced with retroviral particles coordinating expression of ␤-galactosidase (LacZ) and introduced into the adventitia of right carotid arteries of rats immediately after balloon injury. At defined times after injury and fibroblast implantation, rats were euthanized, and arterial tissue was examined for detection of LacZ mRNA (reverse transcription polymerase chain reaction), DNA (polymerase chain reaction), and in situ enzymatic activity. LacZ expression was detected in the media 5 days postinjury and in both media and neointima at 7, 10, and 14 days postinjury. LacZ was undetectable in injured vessels that had not been seeded with transduced fibroblasts and was restricted to the adventitia in seeded vessels that were not injured. Neointima formation also has been observed in response to adventitial injury in various animal models. 3,4 Further, endoluminal injury of the porcine coronary artery has been shown to result in significant remodeling of the adventitia, characterized by proliferation of adventitial fibroblasts. [5][6] Similarly, BrdU labeling studies 7 have demonstrated increased adventitial proliferation within 3 days after endoluminal balloon injury of the rat carotid artery, which progressed over time to the neointimal compartment. Conclusions-TheseThese findings provided indirect evidence for participation of adventitial cells in neointima formation after endoluminal vascular injury, because BrdU cannot selectively identify specific cells of adventitial origin. The inability to identify cells that entered the replicative cycle before or after BrdU administration and decreasing intensity of BrdU staining with time, as a result of the dilutional effect of ongoing cell division, makes it difficult to use this technique over prolonged periods. 8 The current study used a more direct approach to test the hypothesis that adventitial fibroblasts migrate in a luminal direction into the neointima after endoluminal vascular injury. Syngeneic fibroblasts, derived from the adventitia of rat carotid arteries, were stably transduced with a ␤-galactosidase reporter gene and introduced into the adventitia of rat carotid arteries immediately after balloon injury. Results suggest that endoluminal injury of the rat carotid artery induces the migration of fibroblasts from the adventitia, through the medial layer, and into the neointimal compartment. Methods Syngeneic Adventitial FibroblastsPrimary cultures of adventitial fibroblasts 9 were recovered from the carotid arteries of female Sprague-Dawley rats (Charles River, Wilmington, Massachusetts), transduced with retroviral particles encoding ␤-galactos...

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.

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We tested the hypotheses that hypoxic exposure is associated with exacerbated pulmonary hypertension and right ventricular (RV) enlargement, reduced atrial natriuretic peptide (ANP) clearance receptor (NPR-C) expression, and enhanced B-type natriuretic peptide (BNP) expression in the absence of ANP. Male wild-type [ANP(+/+)], heterozygous [ANP(+/−)], and homozygous [ANP(−/−)] mice were studied after a 5-wk hypoxic exposure (10% O2). Hypoxia increased RV ANP mRNA and plasma ANP levels only in ANP(+/+) and ANP(+/−) mice. Hypoxia-induced increases in RV pressure were significantly greater in ANP(−/−) than in ANP(+/+) or ANP(+/−) mice (104 ± 17 vs. 45 ± 10 and 63 ± 7%, respectively) as were increases in RV mass (38 ± 4 vs. 26 ± 5 and 29 ± 4%, respectively). NPR-C mRNA levels were greatly reduced in the kidney, lung, and brain by hypoxia in all three genotypes. RV BNP mRNA and lung and kidney cGMP levels were increased in hypoxic mice. These findings indicate that disrupted ANP expression worsens hypoxic pulmonary hypertension and RV enlargement but does not alter hypoxia-induced decreases in NPR-C and suggest that compensatory increases in BNP expression occur in the absence of ANP.

Hypoxic pulmonary vasoconstriction underlies the development of high-altitude pulmonary edema. Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, we assessed the effect of garlic on pulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of N G-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) inhibited the vasodilatory effect of garlic by 80%. These studies document that garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a combination of endothelium-dependent and -independent mechanisms for the effect in pulmonary arterial rings.