NOX and inflammation in the vascular adventitia

Abstract

Vascular inflammation has traditionally been thought to be initiated at the luminal surface and progress through the media toward the adventitial layer. In recent years, however, evidence has emerged suggesting that the vascular adventitia is activated early in a variety of cardiovascular diseases and that it plays an important role in the initiation and progression of vascular inflammation. Adventitial fibroblasts have been shown to produce substantial amounts of NAD(P)H oxidase-derived reactive oxygen species (ROS) in response to vascular injury. Additionally, inflammatory cytokines, lipids, and various hormones, implicated in fibroblast proliferation and migration, lead to recruitment of inflammatory cells to the adventitial layer and impairment of endothelium-dependent relaxation. Early in the development of vascular disease, there is clear evidence for progression toward a denser vasa vasorum which delivers oxygen and nutrients to an increasingly hypoxic and nutrient-deficient media. This expanded vascularization appears to provide enhanced delivery of inflammatory cells to the adventitia and outer media. Combined adventitial fibroblast and inflammatory cell-derived ROS therefore are expected to synergize their local effect on adventitial parenchymal cells, leading to further cytokine release and a feed-forward propagation of adventitial ROS production. In fact, data from our laboratory and others suggest a broader paracrine positive feedback role for adventitia-derived ROS in medial smooth muscle cell hypertrophy and neointimal hyperplasia. A likely candidate responsible for the adventitia-derived paracrine signaling across the vessel wall is the superoxide anion metabolite hydrogen peroxide, which is highly stable, cell permeant, and capable of activating downstream signaling mechanisms in smooth muscle cells, leading to phenotypic modulation of smooth muscle cells. This review addresses the role of adventitial NAD(P)H oxidase-derived ROS from a nontraditional, perivascular vantage of promoting vascular inflammation and will discuss how ROS derived from adventitial NAD(P)H oxidases may be a catalyst for vascular remodeling and dysfunction.

Fig.1. The known and proposed mechanisms leading to the initiation and progression of vascular disease from an “outside-in” perspective of vascular inflammation

Early in the development of vascular disease, adventitial fibroblasts produce a substantial amount of NAD(P)H oxidase-derived ROS in response to vascular injury, inflammatory cytokines, lipids and various hormones. There is also clear evidence showing that the appearance of microvessels in the form of denser vasa vasorum is an early hallmark of vascular inflammatory disease. Increased levels of adventitial fibroblasts-derived cytokines and ROS would be expected to increase the expression of adhesion molecules on the endothelial lining of an expanded vasa vasorum leading to the transmigration of inflammatory cells to the adventitia and outer media. Invading leukocytes coalesce in the adventitia in response to hormonal stimulants, i.e. AngII, and contribute to the adventitial cytokine and ROS production, thus leading to further increased fibroblast cytokine secretion and a feed-forward propagation of adventitial ROS production. The local cytokine milieu influences the adventitial fibroblasts to undergo a phenotypic switch into myofibroblasts, which migrate to the medial and intimal layer. During neointimal hyperplasia, MCP-1 produced by migratory myofibroblasts is proposed as a chemotactic signal for monocytes leading to their exaggerated transmigration across the vessel wall. In the adventitial layer, resident fibroblasts and inflammatory cells produce superoxide that may be spontaneously or enzymatically dismuted to H₂O₂, which is relatively stable and cell-permeable and thus likely to act as a paracrine mediator across the vessel wall. H₂O₂ and perhaps ONOO^- are postulated to diffuse to the medial layer, where they directly activate smooth muscle cell kinases. This paracrine oxidative signaling is proposed to mediate medial proliferation and hypertrophy and/or initiate activation of medial NAD(P)H oxidase, which indirectly contributes to medial remodeling.

Fig.2

Schematic diagram illustrating the signaling pathways activated by H₂O₂ in vascular smooth muscle cells. As noted in the text, H₂O₂ activates numerous signaling molecules and stimulates NAD(P)H oxidase activity in smooth muscle cells, leading to a feed-forward propagation of signaling mechanisms, increased ROS production and amplification of medial remodeling. Akt/PKB, Akt/protein kinase B; BMK1, big mitogen-activated protein kinase 1; EGF-R, epidermal growth factor receptor; Grb2, growth factor receptor-bound protein 2; JNKs; c-Jun N-terminal kinases; p38 MAPK, p38 mitogen-activated protein kinase, PI3-K, phosphatidylinositol-3 kinase; Shc, src homology complex; Sos, son-of-sevenless.