Vascular Embryology and Angiogenesis

In simple terms, the cardiovascular system consists of a sophisticated pump (i.e., the heart) and a remarkable array of tubes (i.e., the blood and lymphatic vessels). Arteries and arterioles (the efferent blood vessels in relation to the heart) deliver oxygen, nutrients, paracrine hormones, blood and immune cells, and many other products to the capillaries, small-caliber, thin-walled vascular tubes. These substances are then transported through the capillary wall into the extravascular tissues, where they participate in critical physiological processes. In turn, waste products are transported from the extravascular space back into the blood capillaries and returned by the venules and veins (the afferent vessels) to the heart. Alternatively, approximately 10% of the fluid returned to the heart courses via the lymphatic system to the large veins. To develop normally, the embryo requires the delivery of nutrients and removal of waste products beginning early in development, and, indeed, the cardiovascular system functions early during morphogenesis. The fields of vascular embryology and angiogenesis have been revolutionized through experimentation with model organisms. In particular, this chapter focuses on key studies using common vascular developmental models, including the mouse, zebrafish, chick, and chick-quail transplants, each of which has its advantages. Among mammals, the most powerful genetic-engineering tools and the greatest breadth of mutants are readily available in the mouse. Furthermore, the mouse is a good model of many aspects of human vascular development, and, in particular, the vasculature of the mouse retina is a powerful model as it develops postnatally and is visible externally. The zebrafish is a transparent organism that develops rapidly with a welldescribed pattern of cardiovascular morphogenesis and sophisticated genetic manipulations that are readily available. The chick egg is large with a yolk sac vasculature that is easily visualized and develops rapidly. And finally, the coupling of chick-quail transplants with species-specific antibodies allows for cell tracing experiments. The combination of studies with these powerful model systems, as well as others, has yielded key insights into human vascular embryology and angiogenesis. Although blood vessels are composed of three tissue layers, the vast majority of the vascular-development literature has focused on the morphogenesis of the intima, or inner, layer. This intima consists of a single layer of flat endothelial cells (ECs) that line the vessel lumen and are elongated in the direction of flow. Moving radially outward, the next layer is the media consisting of layers of circumferentially oriented vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) components, including elastin and collagen. In smaller vessels, such as capillaries, the mural cells consist of pericytes instead of VSMCs. Finally, the outermost layer of the vessel wall is the adventitia, a collection of loose connective tissue, fibroblasts, macrophages, cells expressing stem-cell markers, and small vessels, known as the vasa vasorum, that perfuse the cells of larger arteries. This chapter summarizes many of the key molecular and cellular processes and underlying signals in the morphogenesis of the different layers of the blood vessel wall and of the circulatory system in general. Specifically, for intimal development, it concentrates on early EC patterning, specification and differentiation, lumen formation, branching, metabolism, and lymphatic vessel morphogenesis. In the second section, the development of the tunica media is divided into subsections examining the components of the media, VSMC origins, smooth muscle cell (SMC) differentiation, and patterning of the developing VSMC layers and the ECM. Finally, the chapter concludes with a succinct summary of morphogenesis of the adventitia, adventitial stem cells, and macrophages. Understanding these fundamental vascular developmental processes is important from a pathophysiological and therapeutic standpoint because many diseases almost certainly involve the recapitulation of developmental programs. For instance, in many vascular disorders, mature VSMCs dedifferentiate and exhibit increased rates of proliferation, migration, and ECM synthesis through a process termed phenotypic switching.