Vascular Extracellular Matrix and Aortic Development
Introduction
With the emergence of a high-pressure, pulsatile circulatory system in vertebrates came a remarkable change in blood vessel structure and function. Blood vessels no longer acted as simple tubes for channeling blood or other body fluids from a low-pressure heart. In this closed circulatory system, large arteries became an important component of proper cardiac function by serving as elastic reservoirs, enabling the arterial tree to undergo large-volume changes with little change in pressure. Without elastic vessels, the tremendous surge of pressure as blood ejected from the heart would inhibit the heart from emptying, and the pressure in the vessels would fall so rapidly that the heart could not refill. Furthermore, distension of the elastic arterial wall by blood pushed from the heart is translated into kinetic energy when the arterial wall contracts, which helps move the blood down the vascular tree. The change that brought about this critical step in the evolution of higher organisms was the emergence of a vascular wall containing cells specialized in the production and organization of an extracellular matrix (ECM) uniquely designed to provide elastic recoil.
In addition to providing the structural and mechanical properties required for vessel function, the ECM provides instructional signals that induce, define, and stabilize smooth muscle phenotypes. There are many examples of ECM molecules playing critical roles in the regulation of gene expression by interacting with specific matrix receptors on cells and by binding and storing growth factors that influence cellular function. This reciprocal instructive interaction between the cell and its ECM is important in directing the developmental transitions that occur in embryogenesis, postnatal development, and in response to injury. How vascular cells interpret these regulatory signals is a major area of research today.
This review will discuss the ECM molecules made by vessel wall cells during vascular development, with the primary focus on the developing mouse aorta. Several excellent reviews have summarized our current understanding of smooth muscle cell phenotypes based on expression of cytoskeletal and other marker proteins (Glukhova 1995, Hungerford 1996, Owens 1995). There are also numerous ultrastructural studies documenting the architecture of the developing vessel wall (Albert 1972, Berry 1972, Gerrity 1975, Haust 1965, Karrer 1961, Paule 1963, Pease 1960, Thyberg 1979), although most of these studies have been in animals other than mouse. The morphogenesis of the aortic wall in the rat, however, has been well investigated (Berry 1972, Cliff 1967, Gerrity 1975, Nakamura 1988, Paule 1963, Pease 1960) and shows many similarities with mouse wall structure (Davis 1993, Karrer 1961). For the interested reader, extensive information on the vascular smooth muscle cell and a still timely discussion of questions and issues driving research in vascular biology can be found in a monograph by Schwartz and Mecham (1995).
Section snippets
Vessel Wall Formation and Structure
While the role of endothelial cells in the formation of the vascular primordia is beginning to be well understood (Carmeliet 2000, Drake 1998, Rossant 2002), surprisingly little is known about how vessels acquire their coat of smooth muscle cells that make up the vessel wall. Presumptive vascular smooth muscle cells (VSMCs) form from the surrounding mesenchyme and⧸or cardiac neural crest in response to soluble factors secreted by endothelial cells. The angiopoietin⧸Tie receptor pathway (Dumont
The Vascular Extracellular Matrix
In addition to the structural matrix proteins (collagen, elastin, proteoglycans, etc.), vascular cells must produce matrix macromolecules that are important for cell movement, polarization, and anchorage. These molecules, which include adhesive glycoproteins such as fibronectin, basement membrane components, and the matricellular proteins that modulate cell–matrix interactions, provide important informational signals to cells that can influence gene expression and cellular function. To identify
Collagens
Collagens are ubiquitous ECM proteins that impart a structural framework to tissues (Mecham, 1998). All collagens have a triple-helical domain that is composed of repeats where glycine occupies every third position in the sequence (Gly-X-Y). Three individual collagen proteins, called α chains, associate to form a righthanded triple helix. The three chains can be identical or consist of two or three different α chains. In all, 17 different collagens were identified in the developing mouse aorta
Elastin
The elastic fiber is a multicomponent structure whose main protein is elastin. In contrast to the genetic diversity evident in the collagen gene family, elastin is encoded by only one gene. Tropoelastin, the monomeric gene product, contains alternating domains of hydrophobic amino acids that contribute to the protein's elastic properties and sequences that contain lysine residues that will serve to cross-link the protein into a functional polymer (elastin). The carboxy-terminal region of the
Fibulins
The fibulins are a family of ECM proteins with five members (Argraves 2003, Chu 2004, Timpl 2003). The amino terminal region of fibulin-1 and -2 consists of an anaphylatoxin-type structure; the midportion contains multiple calcium-binding EGF-like repeats, and the C-terminus contains a motif similar to the fibrillins. Fibulins-3, -4, and -5 lack the anaphylatoxin-type domain. The fibulins are often found in association with elastin fibers and are also known to bind to multiple components of the
EMILIN⧸Multimerin Family
The EMILIN⧸Multimerin family comprises four proteins (EMILIN 1–3 and multimerin) with common structural domains. At the amino terminus is an EMI domain (a cysteine-rich sequence of ∼80 amino acids), a large central region thought to facilitate coiled-coil structures, and a carboxyl-terminal region homologous to the globular domain of C1q that directs the formation of trimers (Colombatti et al., 2000). The function of the EMILINs is largely unknown, although there is accumulating evidence for a
Fibronectin
Numerous studies have illustrated the importance of fibronectin to vessel formation, particularly in the early embryonic periods (Francis 2002, Glukhova 1995, Risau 1988). In the embryonic chicken, the early vasculature is rich in fibronectin but relatively devoid of basement membrane or structural matrix proteins (Risau and Lemmon, 1988). Our expression profile data suggest the same is true in the developing mouse aorta, where fibronectin expression is high and relatively constant throughout
The Basement Membrane
Along with type IV collagen and entactin⧸nidogen, the laminins are the major structural elements of the basement membrane (also referred to as basal lamina) (Ekblom and Timpl, 1996). The molecular architecture of these matrices results from specific binding interactions among the various components. Type IV collagen chains that assemble into a covalently stabilized polygonal network form the structural skeleton. Laminin self-assembles through terminal domain interactions to form a second
Proteoglycans
The proteoglycans constitute a number of genetically unrelated families of multidomain proteins that have covalently attached glycosaminoglycan (GAG) chains. To date, more than 25 distinct gene products have been identified that carry at least one GAG chain (Iozzo and Murdoch, 1996). For historical reasons, proteoglycans are named based on the type of attached GAG chain(s): (1) chondroitin sulfate and dermatan sulfate, consisting of a repeating disaccharide of galactosamine and either
Matricellular Proteins
The term matricellular has been applied to a group of extracellular proteins that function by binding to matrix proteins and to cell surface receptors but do not contribute to the structural integrity of the ECM (Bornstein and Sage, 2002). Proposed members of this group include the thrombospondins, members of the tenascin protein family, SPARC⧸osteonectin, and osteopontin. These proteins are frequently called “antiadhesive proteins” because of their ability to induce rounding and partial
Correlation of Matrix Gene Expression Profile with Cytoskeletal Markers
The most commonly used markers for smooth muscle cell identification are smooth muscle-specific isoforms of contractile proteins. Changes in cytoskeletal organization occur as cells within the vessel wall mature, so characterization of the contractile proteins expressed by these cells provides a useful way of following their phenotypic transitions. The nature of the contractile proteins as well as their expression pattern in the developing arterial wall have been extensively reviewed (Glukhova
Conclusions
The control of vessel wall formation involves the complex interaction of a multitude of signaling events and structural developments. From the earliest hint of an endothelial tube network, extracellular matrix molecules are important to this process. Gene expression analysis of the developing aorta provides evidence for a dramatic phenotypic switch in smooth muscle cells beginning at embryonic day 14, characterized by a major increase in structural matrix protein production. Over a period of
Acknowledgements
The original work sited in this review was funded by grants to R.P.M. from the National Institutes of Health (HL53325, HL62295, HL71960). C.M.K. was supported by Pediatric Cardiology Training Grant T32 HL07873. We would like to thank Terese Hall for expert editorial assistance and Dr. Thomas Mariani and Brigham Mecham at Harvard University for assistance with the microarray analysis. We also thank Russel Knutsen and Marilyn Levy for expert electron microscopy.
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