An important factor in the transition from an open to a closed circulatory system was a change in vessel wall structure and composition that enabled the large arteries to store and release energy during the cardiac cycle. The component of the arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle. Beginning with the onset of pulsatile blood flow in the developing aorta, smooth muscle cells in the vessel wall produce a complex extracellular matrix (ECM) that will ultimately define the mechanical properties that are critical for proper function of the adult vascular system. This review discusses the structural ECM proteins in the vertebrate aortic wall and will explore how the choice of ECM components has changed through evolution as the cardiovascular system became more advanced and pulse pressure increased. By correlating vessel mechanics with physiological blood pressure across animal species and in mice with altered vessel compliance, we show that cardiac and vascular development are physiologically coupled, and we provide evidence for a universal elastic modulus that controls the parameters of ECM deposition in vessel wall development. We also discuss mechanical models that can be used to design better tissue-engineered vessels and to test the efficacy of clinical treatments.

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Vascular Extracellular Matrix and Arterial Mechanics

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be composed of two distinct components, a more abundant amorphous component and a 10-12 nm microfibrillar component, which is located primarily around the periphery of the amorphous component. The protein elastin makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom and possesses an unusual chemical composition rich in glycine, proline, and hydrophobic amino acids, consonant with its characteristic physical properties. The 72-kDa biosynthetic precursor, tropoelastin, is secreted into the extracellular space where it becomes highly cross-linked into a rubber-like network through the activity of the copper-requiring enzyme lysyl oxidase. Analysis of the elastin gene has demonstrated that hydrophobic and cross-linking domains are encoded in separate exons and that there is significant alternative splicing, resulting in multiple isoforms of tropoelastin. The elastin gene promoter contains many potential binding sites for various modulating factors indicative of a complex pattern of transcriptional regulation. The microfibrils contain several proteins, including fibrillin, and probably act as an organizing scaffold in the formation of the elastin network. There appears to be a fibrillin gene family in which each protein contains multiple repeats of a motif previously found in epidermal growth factor and a second motif observed in transforming growth factor beta 1-binding protein. Mutations in the fibrillin gene located on human chromosome 15 have been strongly implicated as the cause of the Marfan syndrome.

Extracellular matrix 4: the elastic fiber.

Ocular and Systemic Pseudoexfoliation Syndrome

The pseudoexfoliation syndrome has recently been suggested to represent the local manifestation of a more widespread disorder. In this study, a case of classic bilateral pseudoexfoliation syndrome with systemic distribution of pseudoexfoliation material involving a variety of organ systems is described. Using transmission electron microscopy, typical pseudoexfoliation fibers were identified in autopsy tissue specimens of skin, heart, lungs, liver, kidney, and cerebral meninges in addition to the classic intraocular locations. The pseudoexfoliation material was mainly localized to connective-tissue portions or septa traversing the various organs. The pseudoexfoliation fibers were consistently associated with connective-tissue components, particularly fibroblasts and collagen and elastic fibers; myocardial tissue specimens; and heart-muscle cells. These findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.

Pseudoexfoliation syndrome, ocular manifestation of a systemic disorder?

Pseudoexfoliation syndrome for the comprehensive ophthalmologist. Intraocular and systemic manifestations.

• Evidence is increasing that pseudoexfoliative material develops in widespread areas of skin and parabulbar tissues as well as intraocularly. To determine whether this process is even more diffusely distributed, ultrastructural examination was performed on visceral and ocular tissues of a patient with longstanding glaucoma found to have bilateral ocular pseudoexfoliation at autopsy. Aggregates consistent with pseudoexfoliative material were present in the lung, heart, liver, and gallbladder, in addition to the classic intraocular sites. The aggregates were in the fibrovascular septa and stroma of these organs, most frequently adjacent to elastic and oxytalan fibers. They stained positively for elastin and human amyloid P protein, like the ocular sites, in preliminary immunologic testing. Rare atypical aggregates were seen in one of the four control patients. These findings suggest that pseudoexfoliation is a systemic process involving abnormal matrix synthesis, particularly as related to elastic tissue components.

Pseudoexfoliative Fibrillopathy in Visceral Organs of a Patient With Pseudoexfoliation Syndrome

Pseudoexfoliative Fibrillopathy in the Skin of Patients by Ocular Pseudoexfoliation

Characterization of an associated microfibril protein through recombinant DNA techniques.

Using immunoelectron microscopy, the presence of elastin and tropoelastin was demonstrated in pseudoexfoliative (PSX) material in all its classical sites on the lens capsule, ciliary non-pigment epithelium, iris epithelium and stroma, and conjunctiva. Some variability in binding affinity was seen in different sites, and labelling was more often on the periphery than the center of the PSX fibers. The elastin epitope on PSX material was more sensitive to processing than the remarkably stable epitope on mature elastic fibers. Since neither elastin nor a related component of PSX fibers, elastic microfibrillar protein, is a circulating protein, both are likely to be secreted by local ocular cells. Most of these local cells are not involved in elastogenesis normally, suggesting that an abnormal stimulus or defective regulation of matrix synthesis exists in this disease.

Association of elastin with pseudoexfoliative material: an immunoelectron microscopic study

Amyloid P protein was demonstrated by immunostaining in all 14 samples of ocular and conjunctival pseudoexfoliative (PSX) material studied, although amyloid was not found by Congo red staining or ultrastructurally. Immunostaining of PSX aggregates for other common amyloid proteins, including amyloid A, prealbumin, and immunoglobulin light chains, was negative in most cases. In three eyes with advanced neovascular glaucoma there was irregular immunostaining of the PSX aggregates for 2-4 of these other amyloid proteins, besides diffuse staining of the iris and vitreous. Control cases of neovascular glaucoma without PSX disease showed minimal amyloid P, but similar tissue staining for prealbumin and immunoglobulin light chains, consistent with an origin from vascular leakage. The presence of amyloid P protein, a minor serum component, in PSX aggregates in all cases with or without evidence of vascular leakage, indicated a more specific association. Ultrastructural localization of the protein on the periphery of PSX fibers suggest it is not an intrinsic fiber component. Since PSX material has an immunological relation to elastic tissue, we propose that PSX fibers have peripheral binding sites for amyloid P protein, similar to those present on normal elastic fibers.

Zong-Yi Li

Papers

Pseudoexfoliative Fibrillopathy in Visceral Organs of a Patient With Pseudoexfoliation Syndrome

Pseudoexfoliative Fibrillopathy in the Skin of Patients by Ocular Pseudoexfoliation

Characterization of an associated microfibril protein through recombinant DNA techniques.

Association of elastin with pseudoexfoliative material: an immunoelectron microscopic study

Amyloid P protein in pseudoexfoliative fibrillopathy.