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Abstract: The adventitial segment of the vessel wall has received limited attention compared the endothelium, media and neointima in processes involved in vascular remodelling during atherogenesis, coronary artery bypass graft failure and in response to angioplasty. The adventitia has been regarded as a relatively ‘inert’ layer providing a supportive connective tissue and extracellular matrix scaffold around vessels for nerves and the vasa vasorum. We and others have recently demonstrated that functional changes in cells within the adventitia contribute to vascular remodelling through the activation and migration of adventitial myofibroblasts, partly under the influence of transforming growth factor-β1 and platelet derived growth factor-BB. These cytokines stimulate local accumulation of progenitor cells, angiogenesis, matrix deposition and enhanced generation of reactive oxygen species, together contributing to intimal hyperplasia in vascular diseases. This review summarises the evidence that growth factors acting locally in the adventitia can influence vascular function. Furthermore we highlight the therapeutic potential of perivascular gene transfer approaches from the ‘outside-in’ to antagonise growth factor activity and to modulate expression of vaso- and redox-active genes which act in concert to prevent the progression of vascular diseases in which adventitial cells are activated. [Copyright &y& Elsevier]

Abstract: The endothelium plays a key role in the maintenance of vascular homeostasis, and increased oxidative stress in vascular disease leads to reduced nitric oxide bioavailability and impaired endothelium-dependent relaxation of resistance vessels. Although epidemiological evidence suggests that diets containing high amounts of natural antioxidants afford protection against coronary heart disease (CHD), antioxidant supplementation trials have largely reported only marginal health benefits. There is controversy concerning the cardiovascular benefits of prolonged estrogen/progestin or soy isoflavone therapy for postmenopausal women and patients with an increased risk of CHD. Research on the potential health benefits of soy isoflavones and other polyphenols contained in red wine, green and black tea and dark chocolate developed rapidly during the 1990''s, and recent clinical trials and studies in animal models and cultured endothelial cells provide important and novel insights into the mechanisms by which dietary polyphenols afford protection against oxidative stress. In this review, we highlight that NO and reactive oxygen radicals may mediate dietary polyphenol induced activation of Nrf2, which in turn triggers antioxidant response element (ARE) driven transcription of phase II detoxifying and antioxidant defense enzymes in vascular cells. [Copyright &y& Elsevier]

Objectives: Migration of adventitial fibroblasts, in addition to smooth muscle cell proliferation, plays a role in neointima formation following vascular injury. Previous studies have not directly addressed whether endogenous adventitial cells migrate towards the intima following balloon injury in the absence of medial dissection. We have employed an in vivo gene transfer technique to the rat carotid artery to directly label adventitial fibroblasts prior to balloon injury. Methods: An adenoviral vector coordinating expression of nuclear targeted β-galactosidase (AdLacZ) suspended in pluronic gel was applied to the perivascular surface of left carotid arteries of male Sprague–Dawley rats. Balloon catheter mediated vascular injury was performed on these arteries 4 days later and animals killed at 3, 7 and 14 days after injury. Results: Expression of LacZ up to 14 days after application of the adenovirus was restricted only to the adventitia of uninjured arteries and absent from untransfected right carotid arteries. However, following balloon catheter injury, LacZ positive cells were observed within the medial layer of vessels by 3 days, and contributed to the population of cells within the neointima at 7–14 days. Adventitial cells in uninjured arteries did not express smooth muscle α-actin but after injury, LacZ positive cells migrating towards the lumen exhibited α-actin immunostaining, suggesting their change to a myofibroblastic phenotype. Conclusions: These findings provide direct evidence that adventitial fibroblasts migrate and contribute to neointima formation after balloon injury and show that in vivo gene transfer to the adventitia results in sustained transgene expression capable of labelling migrating adventitial cells within the media and neointima of injured vessels. [Copyright &y& Elsevier]

Atherosclerosis is a major contributor to cardiovascular disease, and genetic disorders of lipoprotein metabolism are recognized risk factors in atherogenesis. The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated within the blood vessel wall, have been identified as important cellular messengers involved in the regulation of vascular smooth muscle tone. Microsomal heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase have been identified, a constitutive isoform HO-2 (Mr∼34 000) and an inducible isoform HO-1 (Mr∼32 000), which is expressed at a low basal level in vascular endothelial and smooth muscle cells and is induced by heavy metals, oxidative stress, inflammatory mediators and oxidized low density lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet aggregation and smooth muscle relaxation, CO has a much lower affinity for soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in atherosclerosis may be compensated for by an induction of HO-1, with bilirubin acting as a cellular antioxidant and CO as a vasodilator. This review examines the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro-inflammatory cytokines induce HO-1 expression and activity in vascular endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential of the heme oxygenase signalling pathway. [ABSTRACT FROM PUBLISHER]