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Experimental Physiology 90.4 pp 469-475
DOI: 10.1113/expphysiol.2005.030130
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Symposium Report

New aspects of artery resistance and structure

New aspects of vascular remodelling: the involvement of all vascular cell types

John C McGrath1, Clare Deighan1, Ana M Briones1, Majid Malekzadeh Shafaroudi1, Melissa McBride1, Jeremy Adler2, Silvia M Arribas1, Elisabet Vila1 and Craig J Daly1

1 Autonomic Physiology Unit, Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK 2 Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden

Abstract

Conventionally, the architecture of arteries is based around the close-packed smooth muscle cells and extracellular matrix. However, the adventitia and endothelium are now viewed as key players in vascular growth and repair. A new dynamic picture has emerged of blood vessels in a constant state of self-maintenance. Recent work raises fundamental questions about the cellular heterogeneity of arteries and the time course and triggering of normal and pathological remodelling. A common denominator emerging in hypertensive remodelling is an early increase in adventitial cell density suggesting that adventitial cells drive remodelling and may initiate subsequent changes such as re-arrangement of smooth muscle cells and extracellular matrix. The organization of vascular smooth muscle cells follows regular arrangements that can be modelled mathematically. In hypertension, new patterns can be quantified in these terms and give insights to how structure affects function. As with smooth muscle, little is known about the organization of the vascular endothelium, or its role in vascular remodelling. Current observations suggest that there may be a close relationship between the helical organization of smooth muscle cells and the underlying pattern of endothelial cells. The function of myoendothelial connections is a topic of great current interest and may relate to the structure of the internal elastic lamina through which the connections must pass. In hypertensive remodelling this must present an organizational challenge. The objective of this paper is to show how the functions of blood vessels depend on their architecture and a continuous interaction of different cell types and extracellular proteins.

(Received 24 March 2005; accepted after revision 9 May 2005; first published online 12 May 2005)
Corresponding author J. McGrath: Autonomic Physiology Unit, Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Email: i.mcgrath{at}bio.gla.ac.uk

Knowledge of vascular structure is largely based on a long-standing, static view from two-dimensional histology that focuses predominantly on the tunica media with its close-packed smooth muscle cells and extracellular matrix. However, the adventitia and endothelium are now viewed as key players in vascular growth and repair.

Recent work has raised major fundamental questions of vascular heterogeneity and the time course and triggering of remodelling. An integrated view of the inter-relationships of different cell types in forming and maintaining the structure of the arterial walls is made possible by confocal microscopy, which can produce 3-dimensional images of the intact, even living, walls of small arteries. As the data is captured in digital form, it is readily amenable to quantitative analysis using specially designed image-analysis software. Structures can be recognized from their positions in the vascular wall, either visually by the microscopist or automatically. Information can then be derived about their positions, dimensions and characteristics related to intensity of signal, such as receptor density. Quantitative comparisons can then be made between test arteries, related to number and density of objects. A good example is cell nuclei, which are relatively easy to distinguish from each other and which are substantially different between cell types, allowing separate analysis of different cell types (Fig. 1). Complete cells are much more difficult to work with because they make too many contacts with each other, but cell numbers, position and orientation are readily computed from their nuclei. In addition, overall cellular arrangements can be analysed and comparisons made between healthy and diseased vessels (Fig. 1B and C)



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  		Figure 1.  Nuclear stained mouse mesenteric artery
A live segment of artery was mounted on a perfusion myograph and maintained at 70 mmHg. Using laser scanning confocal microscopy, the fluorescence-stained nuclei (syto13; 1 µg ml–1) were excited using the 488 nm line of the argon ion laser. All three cell types (nuclei) are visible. Smooth muscle cell nuclei run vertically. Adventitial nuclei are bright and roughly circular. Endothelial cell nuclei are fainter and are mostly associated with the position of the smooth muscle cells. A, an extended focus projection shows all nuclei. B, a volumetric rendering shows the 3-dimensional nature of the data and enables the vessel curvature to be viewed. C, the image in A has been overlaid with a ‘possible’ path describing the helical nature of the cellular arrangement.

 
The different vascular coats will be considered in turn.

Adventitia

The adventitia, traditionally considered a structural support for the blood vessel is emerging as an important player in the pathogenesis of cardiovascular diseases. When the quantitative analysis of cell numbers and density was applied to hypertensive remodelling, unexpected common denominators that emerged were an increase in adventitial cell density and a decrease in smooth muscle cell density. In addition changes in adventitial cells were one of the earliest signs found (Arribas et al. 1997b; Kantachuvesiri et al. 2001). This suggests that the adventitial cells are drivers of remodelling and may initiate other changes that supersede this, such as alterations in arrangement of smooth muscle cells and extracellular matrix.

The role of the adventitia has recently been highlighted in a number of important cardiovascular diseases as summarized below.

Response and repair following direct injury.  Direct injury, such as angioplasty, triggers a sequence of events involving adventitial fibroblasts, beginning with apoptosis and leading to proliferation and differentiation into myofibroblasts that migrate to the site of injury (Scott et al. 1996; Wilcox et al. 1996; Siow et al. 2003).

Atherosclerosis.  Adventitial reactions (e.g. inflammation and fibrosis) are common in atherosclerotic vessels but are overlooked in favour of studying the media and intima (Gutterman, 1999). Adventitial removal from large arteries results in intimal and medial hyperplasia characteristic of early atherosclerotic lesions (Barker et al. 1994).

Remodelling in hypertension.  Rat models of hypertension (induced pharmacologically, transgenically or genetically) show an increased number of adventitial cells (Arribas et al. 1997a,b; Kantachuvesiri et al. 2001). In mesenteric arteries from the stroke-prone spontaneously hypertensive rates (SHRSP) model adventitial-like cells migrate from the adventitia to the media, as in the response of the adventitia to direct injury. Recently the adventitia has been shown to be the most sensitive layer of the blood vessel in responding to elevations in blood pressure (Schulze-Bauer et al. 2002).

Fibroblasts are the main adventitial cell type implicated in vascular remodelling. Their primary response, which may be common to several cardiovascular diseases, is proliferation and migration. Adventitial fibroblasts can migrate after they differentiate into myofibroblasts (Scott et al. 1996; Wilcox et al. 1996; Siow et al. 2003). This phenotypic transformation is part of the response of the vessel to injury (Zhang et al. 2002; Siow et al. 2003), which also occurs in culture (Patel et al. 2000). The mechanism is unknown but is likely to involve neuroendocrines receptors.

Adventitia and oxidative stress.  The vascular adventitia is an important source of reactive oxygen species. It is therefore fundamental in regulating vascular oxidative stress. This involves both the release of cytokines from adventitial cells and the diffusion of reactive species, both of which can influence smooth muscle cells as well as further actions from activated adventitial cells (Lassègue & Clempus, 2003; Fortuño et al. 2005; Touyz, 2005).

Adventitial {alpha}1-adrenoceptors.  Adventitial cells possess G-protein-coupled receptors whose physiological roles are not known. However, a role in driving structural change by directing effects of the adventitial cells seems an obvious avenue to pursue. As an example, recently the {alpha}1-adrenoceptor family of neuroendocrine receptors were identified on the adventitia of rat and mouse arteries. Unexpectedly, the expression levels in the adventitia (Northern Blots and radioligand binding in rat aorta) were as high as in the media (Faber et al. 2001) and visualization techniques employing fluorescent ligands (Pediani et al. 2000, 2005; Daly & McGrath, 2003; Deighan et al. 2004; Miquel et al. 2005; McGrath & Daly, 2005) showed the density of receptors within adventitial cells to be greater (McGrath et al. 2002). Using mice lacking both the {alpha}1B and {alpha}1D-adrenoceptor ({alpha}1BD double knockout) it was possible to visualize the remaining {alpha}1A-adrenoceptors in adventitial cells of the mouse tail artery (Fig. 2). It was interesting to observe that not all adventitial cells contained {alpha}1A-adrenoceptors, indicating a further basis for different adventitial phenotypes.



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  		Figure 2.  The {alpha}1-adrenoceptor ligand BODIPY-FL-PRAZOSIN (QAPB) (1 µM) binding to {alpha}1A -adrenoceptors in adventitial cells in the tail artery from an {alpha}1BD-knockout (KO) mouse
QAPB is visible as bright spots in some cells (broken arrows). In other cells, there was no QAPB binding and only the nucleus is visible (solid arrows). Autofluorescent elastin fibres are clearly visible running along the length of the vessel.

 
As adventitial fibroblasts do not have conventional contractile capabilities, what is the function of these {alpha}1-adrenoceptors? Noradrenaline stimulates proliferation and migration of adventitial fibroblasts in vitro (Zhang & Faber, 2001; Zhang et al. 2002), key components of the vascular remodelling associated with an injured blood vessel (Sartore et al. 2001). Proliferation was augmented by injury but inhibited by {alpha}1-adrenoceptor antagonists, as was migration of adventitial fibroblasts. An in vivo study indicated that basal noradrenaline does not have trophic or chemotactic effects in an uninjured vessel (Erami et al. 2002). However noradrenaline augmented neointimal formation and adventitial thickening, characteristics of remodelling, in the injured vessel. These studies, in rats, pursue the concept that stimulation of {alpha}1-adrenoceptors will generate a trophic response when an injury is present. This work points to potential physiological roles of adrenoceptors and other modulators of vasomotor tone as exerting trophic actions via the adventitia. Indeed when noradrenaline is infused systemically in mice, the resulting ‘hypertensive remodelling’ in mesenteric arteries does not occur in mice lacking the gene for the {alpha}1B-adrenoceptors (Vecchione et al. 2002). While no specific site was proposed for this action (or lack of action) the adventitial cells must be considered as a strong possibility. In this same knockout mouse strain, lacking the {alpha}1B-adrenoceptors, the number of adventitial cells in tail arteries was reduced, suggesting that {alpha}1B-adrenoceptors are necessary for their proliferation (Daly et al. 1998; Fig. 3). Taken together, these point to an active role of {alpha}1-adrenoceptors in the growth and development of small arteries.



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  		Figure 3.  Representative images of the adventitial cell nuclei in the isolated tail artery from wild-type and {alpha}1B-KO mice
A, wild-type mouse isolated tail artery. B, isolated tail artery from {alpha}1B-KO mice. The black spots represent individual nuclei. Note the relative scarcity in the KO sample.

 
Smooth muscle cell organization

At the level of the arteriole, where the media consists of a single layer of cells, smooth muscle cell organization is relatively simple. The small diameter of the arteriole and the length of a smooth muscle cell (100 µm) enable the cell to wrap completely around the lumen. However, to ensure that the cell tips do not overlap, the cell is set at a slightly acute angle, therefore creating a partial helix. The next cell completes the helix and so on giving a general helical or spiral appearance to the organization.

In resistance arteries, where there are multiple cell layers and a wider lumen, individual smooth muscle cells are set close to perpendicular (± 10 deg) with the axis of flow. However, the smooth muscle cells are positioned in a diagonal offset pattern which creates the helical arrangement using groups of cells (Daly et al. 2002; Fig. 1C). Functionally, this ‘spring like’ organization facilitates lengthening of the vessels when the pressure is high (i.e. during systole). This dampens the pulse-wave velocity and protects the heart from any pressure-induced kick back.

The general organization of vascular smooth muscle cells can be modelled mathematically, for example using fractal dimensions and pattern analysis (Shang et al. 2000). In addition, information derived from Fourier transforms of image data can be used to assist in the modelling of vascular structure (Fig. 4). The ultimate goal would be to determine formulae that describe the arrangement of smooth muscle cells. At present we do not know how much (if any) of the smooth muscle cell arrangement is random and how much is intimately tied to the location of other cell types and matrix structures. It is therefore important to gain a deeper understanding of ‘normal’ 3-dimensional structure and cellular organization models before making judgements about ‘remodelled’ vessels.



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  		Figure 4.  Modelling vascular cell arrangement
Viewed from a relatively low magnification, the vascular smooth muscle cells can sometimes appear to be randomly distributed and sometimes in a spiral or helical arrangement (left). To model the cell distribution it is necessary to derive some form of mathematical description or reduce the overall complexity. The Fourier transform of the blood vessel image (middle) describes the frequency and strength of direction inherent in the image. This type of information can then be used to help construct theoretical models of vascular structure. A simple vascular structure is shown (right). See Daly et al. 2002.

 
In hypertension, the remodelling process produces new patterns of cell and matrix arrangement. Advanced image-analysis and microscopy methods enable these features to be quantified in terms of cell numbers, orientations, locations and viability. Detailed 3-dimensional comparisons between normotensive and hypertensive vessels can thus give insights into how structure affects function.

Endothelium

As with smooth muscle, little is known about the 3-dimensional organization of the vascular endothelium, or its role in vascular remodelling. There are two major aspects to consider: (1) the form of the tubular endothelial ‘layer’; and (2) the relationship of endothelial and underlying smooth muscle cells.

The tube.  A neglected aspect of the endothelium is how it relates to the ridged nature of the intima. This is familiar to the histologist as the corrugated pattern that follows the ‘collapsed’ shape of the internal elastic lamina. However, when the internal elastic lamina is viewed in 3-dimensions in an artery held at physiological pressures, it is seen as longitudinal ridges that remain until the vessel is pressurized towards the top of the physiological range. This presents challenges to the endothelial cells in maintaining their shapes and in maintaining their connections both to each other and to smooth muscle cells via myoendothelial connections. Greensmith & Duling (1984) pointed out the consequences of this for the smooth muscle cells on the inside of the internal elastic lamina: the effects on the endothelial cells are correspondingly serious. For example this could be a factor in hypertension-induced endothelial dysfunction.

Do endothelial cells and underlying smooth muscle cells occur at random?.  Observation of the 3-dimensional relationship suggests that there may be a close relationship between the helical organization of smooth muscle cells and the underlying pattern of endothelial cells. Intuitively, this seems inevitable as the cells ‘talk’ to each other via myoendothelial junctions, and endothelial factors are known to have trophic effects on the underlying cells.

From a developmental viewpoint the relationship between endothelial cells and smooth muscle cells stems from their initial attraction. During the process of vasculogenesis, angioblasts (the endothelial cell precursors) are formed first and are attracted (or delivered) to the required site to create an endothelial tube. Next, the precursor smooth muscle cells are attracted to overlay the endothelial tube. Therefore, from this earliest stage there must be a physical interaction between both cell types and their relative positions are intimately linked. This initial process involves a complex array of growth factors and other processes which are reviewed elsewhere (Hungerford & Little, 1999; Carmeliet & Jain, 2000).

Using image-analysis methods we have shown examples of endothelial cell and smooth muscle cell positions in rat mesenteric arteries where the positions of the endothelial cell nuclei directly overlap those of the smooth muscle cell nuclei (Daly et al. 2000, 2002). Such a relationship in normal vessels is not surprising and the presence of myoendothelial junctions is well established. However, the internal elastic lamina, which separates the endothelial cells from the smooth muscle cells, is now known to be a non-static structure and changes here could lead to significant alterations in myoendothelial communication and thus overall vessel function (see below and accompanying paper by Arribas et al.)

The role of the extracellular matrix in vascular remodelling

It has long been known that, in resistance arteries, the endothelial and smooth muscle cells are kept apart by the tightly woven tube of the internal elastic lamina. The two cell layers are attached on either side of this lamina and can connect only through small windows (fenestrae) in the lamina. However, the structural role of the internal elastic lamina had not been appreciated until 3-dimensional confocal observations were made and related to the biophysical properties of the artery. This became apparent on finding that the spontaneously hypertensive rat (SHR), a genetically hypertensive rat strain, has a radically altered internal elastic lamina structure. In the young adult SHR, the fenestrae are normal in number but are smaller with, on average, one-third of the cross-sectional area of those in normotensive, Wistar-Kyoto (WKY) rats (Briones et al. 2003). This study also showed that the hypertensive rat arteries were stiffer than those of the normotensive rats, and, crucially, that the difference in stiffness was eliminated by destroying the internal elastic lamina with elastase. This shows that the internal elastic lamina represents a core, primary aspect of the architecture of resistance arteries around which the smooth muscle cells are attached, in turn determining their geometry and hence the consequences for the vascular lumen when they contract.

It now seems inevitable that the structural proteins in the arterial wall will receive more attention. The structure can be appreciated as radiating from the internal elastic lamina, followed by the intracellular cytoskeleton of the smooth muscle cell, with the extracellular matrix providing a smart glue between cells, capable of directed re-organization, and ending with the external elastic lamina, which supports the adventitia. The adventitial cells do not appear to be part of the structure that holds the tube together. Rather, they are best placed to have a regulatory role, releasing cytokines and providing a cellular reserve that can differentiate and migrate to sites of injury. However another possible function is sensory. Resistance arteries possess sensory nerves in the outer adventitia that may detect changes in the vessel's dimensions and take part in a local reflex adjustment (Scotland et al. 2004). These nerves have populations of adrenoceptors which may modulate their function (Fig. 5).



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  		Figure 5.  QAPB (1 µ m), a fluorescent ligand for {alpha}1-adrenoceptors, binding to a nerve on the outer surface of a mouse mesenteric artery
The image is a 3-dimensional reconstruction; nerves of this type are virtually undetectable in 2-dimensional sections.

 
Intracellular connections

Tight junctions between cells must be maintained during vascular contraction whereas they must be broken and remade during remodelling. This suggests a very carefully controlled defensive structure for intracellular connections that is capable of withstanding the acute stresses of normal function, but which must be capable of modification to adapt to a new state when the biophysical conditions dictate this. However, as hypertension is a pathological state to which the organism is not well adapted, it is possible that some of the deleterious consequences are associated with the loss of functional cell connections that are sacrificed as a consequence of defending.

Taken together, these issues provide an exciting new phase in understanding the physiological modelling of the vascular wall and how it may go wrong. The 3-dimensional relationships between the different cell types, and between them and the extracellular structure, produces a new view of the dynamic nature of vascular structure.

References

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Acknowledgements

This work was carried out with the support of the European Commission (VASCAN, QLG1-CT- 1999–00084 and QLRI-CT- 2000-60058-15), the British Heart Foundation (Fellowships to Clare Deighan and Melissa McBride) and Tenovus Scotland.




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