Extracellular Matrix Remodeling in Vascular Development and Disease
Blood vessels constantly subjected to mechanical stress have well-developed elastic fiber-rich frameworks, which contribute to the elasticity and distensibility of the vascular wall. Destruction of the fibrous structure due to genetic predisposition as well as acquired disorders such as Kawasaki disease often induces irreversible dilation of blood vessels, e.g., aneurysm formation. In addition to their structural role, extracellular matrix molecules also provide important biological signaling, which influences various cellular functions. Among them, increased attention has been focused on matricellular proteins, a group of nonstructural extracellular matrix (ECM) proteins highly upregulated in active tissue remodeling, serving as biological mediators by interacting directly with cells or regulating the activities of growth factors, cytokines, proteases, and other ECM molecules. Tenascin-C (TNC) is a typical matricellular protein expressed during embryonic development and tissue repair/regeneration in a spatiotemporally restricted manner. Various growth factors, pro-inflammatory cytokines, and mechanical stress upregulate its expression. TNC controls cell adhesion, migration, differentiation, and synthesis of ECM molecules. Our recent results suggest that TNC may not only play a significant role in the recruitment of smooth muscle/mural cells during vascular development, but also regulate the inflammatory response during pathological remodeling. TNC may be a key molecule during vascular development, adaptation, and pathological tissue remodeling.
KeywordsTenascin Extracellular matrix Coronary artery Aorta
Tissue, including the cardiovascular system, is composed of diverse cells and the extracellular matrix (ECM) synthesized by those cells. Several ECM molecules form a fibrous framework and provide structural support for the tissue. Blood vessels constantly subjected to mechanical stress have a well-developed fibrous framework, which contributes to the elasticity and distensibility of the vascular wall in concert with vascular smooth muscle cells. Highly ordered structures consisting of cells and fibrous elements are formed during development and are remodeled during tissue repair/regeneration after injury. In addition to their physical role, several ECM molecules provide important biological signaling, which influences various cellular functions in physiological and pathological tissue remodeling. In particular, ECM, termed matricellular protein, has attracted increasing attention as a biological mediator. Tenascin-C (TNC) is a prototype matricellular protein expressed during embryonic development and tissue repair after injury. This chapter will focus on the role of TNC in vascular development, especially coronary arteries and the aorta.
29.2 Extracellular Matrix in Vascular Wall
Blood vessels have abundant fibrous matrix tissue: well-developed elastic fibers in the medial layer and rich collagen fibers in adventitia. It is known that several gene mutations related to these fibrous components cause vascular fragility, eventually leading to aneurysm formation or dissection. For example, the collagen gene and fibrillin-1 gene, which is important for microfibril formation, have been identified as the genes responsible for Ehlers-Danlos syndrome (reviewed in ) and Marfan’s syndrome , respectively. In addition to genetic predisposition, inflammation of blood vessels in acquired disease may induce fragmentation and destruction of normal elastic fibers in the vascular wall and causes irreversible dilation of blood vessels. For example, coronary aneurysm formation is sometimes seen in patients with Kawasaki vasculitis, one of the most common acquired heart diseases in children. Evidently, the structural support by fibrous ECM is essential to maintain the proper morphology and function of blood vessels.
Besides these fibrous elements, unique ECM molecules, matricellular protein , have attracted considerable attention. The matricellular proteins have common unique properties: (1) do not contribute directly to structures such as fibrils or basement membranes; (2) high levels of expression during embryonic development and in response to injury; and (3) binding to many cell surface receptors, components of ECM, growth factors, cytokines, and proteases . This is a growing family originally including SPARC, tenascin, and thrombospondin .
29.3 Tenascin-C in Vascular System
Tenascins are a family of four multimeric extracellular matrix glycoproteins: tenascin-C, X, R, and W . The first member, tenascin-C (TNC), is a typical matricellular protein. It is a huge molecule of about 220–400 kDa as an intact monomer and is assembled with a hexamer. The molecule consists of an N-terminal assembly domain, followed by EGF-like repeats, constant and alternatively spliced fibronectin type III repeats, and a C-terminal fibrinogen-like globular domain. Several receptors including integrins, EGFR, annexin II, syndecan-4, and toll-like receptor 4 (TLR-4) bind to the respective domains of TNC and transmit multiple signals (see ). Numerous studies have shown that TNC can control the balance of cell adhesion and de-adhesion, cell motility, proliferation, differentiation, and survival (reviewed in [5, 6, 7]). Recently, the role of TNC in the modulation of inflammation is highlighted .
Tenascin-C is found in many developing organs, including the cardiovascular system, but is often restricted transiently to specific sites, for example, near migrating cells and at sites of epithelial–mesenchymal/mesenchymal–epithelial transition. In normal adults, tenascin-C expression is sparsely detected; however, marked expression is seen in injury, regeneration, and cancer at sites where the tissue structure is being dynamically remodeled. Various factors, including growth factors and pro-inflammatory cytokines, can activate TNC expression (reviewed in ). It is particularly of interest that mechanical stress is an important inducer of TNC. Moreover, it is also noteworthy that TNC itself is an elastic molecule and may contribute to tissue elasticity .
As well as in other tissue, the expression of TNC in the normal vascular wall is low and upregulated in pathological conditions. The major source is medial smooth muscle cells . However, TNC in the vascular system appears more complex in contrast to the heart . For example, constitutive expression of TNC is observed in the medial layer of the abdominal aorta of normal adult mice but not in the thoracic aorta .
29.3.1 Development of Aorta and Tenascin-C
29.3.2 Development of Coronary Artery and Tenascin-C
29.4 Future Direction and Clinical Implications
The characteristic spatiotemporally restricted expression of TNC has suggested its significant role during embryonic development. Several in vitro functional assays support this possibility. Although the grossly normal phenotype of knockout mice suggests the importance of redundancy and compensatory mechanisms during embryonic development, it is not straightforward to understand its molecular function. Meanwhile, TNC expression is linked to a range of vascular diseases, such as aortic aneurysm, acute aortic dissection, and Kawasaki disease (reviewed in [11, 17], also see Yoshikane et al. in this proceeding). Increasing numbers of studies have reported that TNC is highly upregulated, associated with inflammation and destruction of the vascular wall, suggesting that TNC may be a diagnostic biomarker. Furthermore, we have succeeded in endovascular treatment of a rat aneurysm model with a TNC-coated coil . Although TNC could contribute to both favorable and undesirable effects during pathological processes in a context-dependent manner, it could be a potential therapeutic target for vascular disease .
The author thanks M. Hara and M. Namikata for providing technical assistance. This work was supported in part by a research grant for intractable diseases from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
- 1.Byers PH, Murray ML. Ehlers-Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol. 2014;33:10–5.Google Scholar
- 5.Chiquet-Ehrismann R, Tucker RP. Tenascins and the importance of adhesion modulation. Cold Spring Harb Perspect Biol. 2011;3.Google Scholar
- 11.Imanaka-Yoshida K, Yoshida T, Miyagawa-Tomita S. Tenascin-c in development and disease of blood vessels. Anat Rec. 2014;297:1747–57.Google Scholar
- 12.Kimura T, Furusho A, Ito S et al. Tenascin c protects aorta from acute dissection in mice. Sci Rep. 2014;4:4051.Google Scholar
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