e32 Arterioscler Thromb Vasc Biol August 2015 media is organized in layers of smooth muscle and crosslinked elastin called lamellae. 25 The number of layers present in conduit arteries is established by midgestation and is characteristic of the position of the artery in the mechanical wall strain profile of the arterial circulation. 25–27 After birth, the overall geometry of the artery wall changes substantially in response to pathophysiological demands. For example, pulmonary hypertension (PH) is characterized by significant increases in pulmonary vascular resistance that results from excessive medial cell proliferation, inward remodeling, and robust adventitial fibrosis. 28 Reactive oxygen species have been proposed as major pathogenic stimuli for PH with the nicotinamide adenine dinucleotide phosphate oxidase family of enzymes, particularly nicotinamide adenine dinucleotide phosphate oxidase-4, as a prominent source of reactive oxygen species in the pulmonary artery wall. 29 Elevated expression of nicotinamide adenine dinucleotide phosphate oxidase-4 was found in intima and adventitia in pulmonary arteries from 3 different rat models of PH and from patients with PH. 29 Small molecule inhibitors of nicotinamide adenine dinucleotide phosphate oxidase-4 were found to reduce adventitial reactive oxygen species production, inhibit inward wall remodeling, and diminish indices of adventitial stiffness as indicated by morphometry and high-resolution ultrasound. 29 Adventitial fibrosis is a common response to sustained elevations of wall stress associated with hypertension. It is also associated with obesity where it is correlated with increased inflammation in PVAT and elastin fragmentation in the aortic wall. 30 These changes in wall structure were associated with decreases in lysyl oxidase activity suggesting that elastin fragmentation and adventitial fibrosis may be linked to reductions in lysyl oxidase activity and PVAT inflammation in settings of obesity. 30 Progressive cardiac fibrosis is characteristic of the late stages of cardiomyopathy in Duchenne muscular dystrophy. Fibrotic tissue extends throughout the myocardium but conspicuously seems to radiate outward from the coronary adventitia. Indeed, using the mdx mouse model of Duchenne muscular dystrophy, cell types responsible for extensive perivascular fibrosis were found to express markers either of cardiac fibroblasts or of adventitial stem cell antigen-1 (Sca1)–positive vascular progenitor cells (AdvSca1 cells). 31 Although the former are not surprising, the finding that major producers of type I and type III fibrillar collagens in the mdx heart were resident adventitial progenitor cells was unexpected and pointed to a pathogenic role for these cells in cardiomyopathy associated with muscular dystrophy. 31 Aortic stiffening is commonly found in hypertensive arteries, and experimental hypertension is associated with inflammation of the adventitia and perivascular tissues. A link between aortic stiffening, adventitial inflammation, and high blood pressure was uncovered by Guzik et al8 who found that resident T cells in the adventitia were activated by neoantigens formed in aortic adventitia of angiotensin II–infused mice and were key mediators of angiotensin II–induced hypertension. Activated adventitial T cells produced locally acting cytokines that resulted in adventitial collagen production, aortic wall stiffening, and the onset of hypertension. 8 Mice deficient in production of the T-cell–derived cytokine interleukin-17a were protected against angiotensin II–induced aortic wall stiffening, adventitial fibrosis, and high blood pressure. 32 Another player in the production of perivascular fibrosis is the pericyte …