Collateral artery growth: making the most of what you have.

The primary role of the vascular system is to carry blood and oxygen to tissue. This task is complicated by the vastly differing needs of tissues for oxygen according to their metabolism. Moreover, the metabolic activity in a given organ, and thereby its need of blood flow and oxygen, may dramatically change in time scales varying from seconds (during the onset of muscular exercise for example) to months or years (growth of organs, ischemic processes). Therefore, to ensure good organ function, the vasculature must adapt to these heterogeneous needs. Because blood vessels are highly distributed in space, one marvels at how a vascular bed manages to adapt structurally to the local environment, and how individual segments within the vascular network succeed in supplying the right amount of blood and oxygen to tissues in the most economical way. In fact, such intricate control requires 2 adaptation processes that exist in parallel: short term release of vasoactive agonists or changes in vascular tone provide a quick functional adaptation to accommodate rapid changes in metabolic demand, whereas growth or regression of blood vessels (termed vascular remodeling) represent long term structural adaptation to new, lasting metabolic and blood flow conditions (Figure 1). Both acute and chronic adaptations are complementary and are driven by the same environmental variables, which include local oxygen tension, vascular wall tension, and shear stress. For example, when arteries remodel in response to a new and lasting elevated blood flow, the initial acute vasodilation, mediated by endothelium-derived nitric oxide (NO) in large arteries and possibly involving prostaglandins in the microvasculature, leads the way to expansive medial remodeling that alters the resting diameter of the vessel. However, simple vasodilatory or remodeling processes may not always be sufficient to meet local needs; when blood flow rates are too small to provide enough oxygen to tissues, tissue hypoxia occurs. To compensate for such metabolic strain, angiogenic processes are likely to be activated, generating neo-vessels, mainly capillaries, small arterioles, and venules. Alternatively, in the situation where an existing artery is stenosed or occluded, the development of existing collateral vessels may be activated. Collateral blood vessels were first described in the limbs by Longland 1and in the coronary circulation by Fulton,2 in the middle of the last century. A body of evidence has since been collected showing that the mechanisms leading to the development of large collateral vessels capable of conducting blood efficiently differ from those usually involved in angiogenesis. Consequently, the term “arteriogenesis” was established to encompass both angiogenesis and collateral growth, recognizing the pivotal differences between these processes.3–5 The association of blood flow with arterial remodeling has been researched using different experimental techniques and conditions. In this regard, one of the most comprehensive models to investigate small artery response was developed by Jo de Mey.6 Persistent changes in blood flow were induced in juvenile rats by ligating every other first-order side branch of the superior mesenteric artery distally, near the bifurcation of second-order branches. Thus, open arteries were exposed to high flow (roughly twice that normally observed), while occluded mesenteric arteries had practically no blood flow. This chronic low flow resulted in decreased passive lumen diameter, hypotrophy of the artery wall, and both loss and atrophy of smooth muscle cells. On the contrary, high flow led to increased lumen diameter and artery wall hypertrophy. Completion of the vascular remodeling process required 16 days in both low-flow and high-flow arteries, and both conditions were associated with apoptotic cell death.7 A major role for the RhoA/Rho kinase system in flow-related small artery remodeling was also established using his experimental model.6 Moreover, the same surgical model was adapted to mice to study the extracellular matrix and cellstructural proteins involved in the mechanotransduction of shear stress. It was shown that resistance arteries of mice lacking the gene encoding for dystrophin do not adapt properly to a chronic increase in flow, inasmuch as the increases in diameter, endothelial NO synthase expression, and flow-mediated dilation do not occur.7 In contrast, excessive structural adaptation to changes in blood flow was described in mice lacking gene encoding for desmin.10 The molecular mechanisms by which shear stress acts on the vessel wall, stimulating the endothelium, has been extensively studied in vitro. The main receptors and signaling cascades induced by shear stress in endothelial cells are summarized in Figure 2.11 Many of these pathways are involved in acute and chronic responses to changes in blood flow, among which NO plays a predominant role. Shear stress is not only the most important physiologic activator of endothelial NO production, but it has been shown to increase endothelial NO synthase (eNOS) expression. In addition, studies from different laboratories reported between 40 and The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Center Inserm Lariboisière, Inserm U689, University Paris 7 Correspondence to Bernard Lévy, Inserm U689, Cardiovascular Research Center Inserm Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France. E-mail [email protected] (Circ Res. 2006;99:567-569.) © 2006 American Heart Association, Inc.