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Collagen and hypertension

Deinum, Jaap

Editorial commentaries
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Department of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Correspondence and requests for reprints to Jaap Deinum, Department of Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. Tel: +31 10 4633089; fax: +31 10 4634531; e-mail: deinum@inw1.azr.nl

In man, cardiovascular complications of hypertension are associated with structural changes in blood vessels and the heart. One of these alterations is an increase in the thickness of the media, which is caused by increased cell mass and increased deposition of extracellular matrix. An important component of the latter is collagen, and this may cause an increase in stiffness of the vessel wall. The hypertrophic response of the vessel wall occurs early in the course of hypertension [1]. It is thought to be beneficial for endothelial and smooth muscle cells as a thicker vessel wall reduces wall tension when blood pressure is increased. In the long term, however, hypertrophy of the vessel wall, as measured for example in the carotid artery, and increased stiffness of the conduit arteries are independent risk factors for cardiovascular disease, especially for stroke [2]. Whether there is a direct causal relation between these structural and mechanic changes and cardiovascular disease remains to be determined. A similar process of cellular hypertrophy with fibrosis (or collagen deposition) in response to hypertension occurs in the heart [3], leading to a stiff ventricle and hence to diastolic heart failure. The two major collagens of the vasculature and heart are type I and type III collagen [3]. Both are fibrillar collagens, with type I forming thick bundles and type III being more reticulate. Increased circulating levels of the procollagen peptides of these two types reflect an increased deposition of these collagens in hypertension-induced myocardial fibrosis. Upon treatment of hypertension with lisinopril, these levels decrease concomitantly with amelioration of cardiac structure and function [4].

It is generally thought that, in hypertensive subjects, collagen deposition in the heart and blood vessels occurs in response to an increase in mechanical load of vascular cells [3]. This mechanical stimulation may lead to increased production of growth factors, or it may have a direct effect on vascular growth through a complex signalling system initiated by mechanosensors.

In hypertensive humans, the small arteries that determine vascular resistance also display collagen accumulation [5] and a structural change consisting of a smaller lumen with an identical media volume, for which the term eutrophic remodelling has been coined [6]. This structural alteration might contribute to the increase in vascular resistance that is the hallmark of hypertension. Folkow [7] and Lever and Harrap [8] put forward hypotheses suggesting that this hypertrophy of resistance vessels is the factor that perpetuates hypertension once an initiating pressor event has abated. This would explain why in some forms of secondary hypertension, such as, for example, a renal artery clip, hypertension may persist after removal of the clip. The processes that lead to this vascular remodelling have been studied extensively in rats. They comprise apoptosis, inflammation and fibrosis that are inducible by various stimuli in addition to blood pressure. Among these are angiotensin II and endothelin-1 [9]. However, few data are available in man.

In the overview above, the deposition of collagen, and the fibrotic process in general in the heart and large vessels, is considered as one of the factors leading to vascular and cardiac morbidity in hypertensive patients. In contrast, hypertrophy of the resistance vessels is seen as a factor that plays a role in sustaining hypertension. Whether the mechanisms leading to this hypertrophy with fibrosis are identical in the various parts of the vascular tree is unknown. Neither do we know whether some individuals are more prone to develop structural alterations when hypertensive compared to others.

In this issue of the journal, Delva et al. [10] embrace the issues raised by Folkow, Lever and Harrap, and Mulvany [11] on the pathogenesis of essential hypertension. Delva and colleagues provide ‘molecular’ evidence to indirectly support the hypothesis that structural changes in resistance arteries of vascular hypertrophy are due to an innate property of fibroblasts to proliferate and synthesize collagen, although the authors do not make the connection with resistance vessels. They obtained fibroblasts from subcutaneous tissue of hypertensive and normotensive subjects. When grown in the presence of fetal serum, fibroblasts from hypertensive individuals had 40% higher expression of collagen type III mRNA than fibroblasts derived from normotensives, but no increase of type I mRNA. Collagen protein expression was also increased by some 30% in these cultures. They also observed increased tritiated thymidine incorporation and expression of a histone, H3, mRNA, which they took as proof of increased proliferation. Fibroblast properties did not correlate with cardiac dimensions, although hypertensive subjects had a significantly higher left ventricular mass. Because these observations were made in cultured cells after several passages Delva et al. [10] concluded that this in-vitro phenotype of increased collagen expression and proliferation is persistent. Therefore, this phenotype may be genetically determined in this cell type in hypertensive individuals. Hence, increased proliferation of fibroblasts and collagen type III deposition is probably a pathogenetic factor in hypertension, rather than a consequence of hypertension.

Although fresh evidence, especially when obtained from human cells, may enliven discussion on the pathogenesis of hypertension, more proof is needed to make it convincing. First, the data are indirect and would be strengthened if they were related to morphometric data of the tissue studied. Because the subjects had already developed hypertension, the increased proliferation of fibroblasts and deposition of collagen should have been operative for a while. Because, in the development of hypertension, the small arterioles are instrumental in augmenting vascular resistance, any observed change in the structure of resistance arteries might have strengthened their claim. Unfortunately, the authors could only use their biopsy material for culture. Instead of histological examination, they took ultrasound-derived measurements of cardiac dimensions to assess in-vivo effects of fibroblast activity. They did not find any correlation of these cardiac dimensions with in-vitro phenotype of fibroblasts. This is not surprising, however, because a major part of increased cardiac mass is due to hypertrophy of cardiomyocytes. A measure of myocardial stiffness, which may be a more appropriate assessment of collagen accumulation, is not given. Second, an expression phenotype may persist in culture for various passages even if this phenotype is not dictated by genetic mechanisms [12]. Examples exist for human vascular smooth muscle cells exposed to pulsatile stress in culture and derived from either internal mammary artery or arterialized saphenous vein. Different production of collagen remained after several passages even though the genetic make-up of cells and the mechanical stimulus were identical [13]. Therefore, a genetic cause is by no means certain. Hence, in the study by Delva et al., where cells were studied after passage 3, the phenotype of collagen deposition and fibroblast proliferation may have been induced by the mechanic factor, hypertension itself, or by local growth factors that have been proposed as mediators between mechanical load and vascular hypertrophy. The latter is more likely because it is not certain from the way fibroblasts have been isolated that they have been subjected to blood pressure directly. Many questions remain on the mechanisms of small vessel hypertrophy and its effects on blood pressure. How could increased collagen type III deposition alter resistance vessel structure? What effect does collagen deposition have on the mechanical properties of small vessels, of which we know that their stiffness is decreased rather than increased? [5]. It is known that fibroblasts play a role in the structural changes of large arteries, but what is their role in the remodelling of small vessels? What is the effect of antihypertensive therapy on collagen production and the growth potential of fibroblasts of resistance arteries? Is there any relationship between collagen production and the presence of angiotensin or endothelin? The contribution by Delva and colleagues is welcome but is still far from being conclusive concerning the role of collagen in hypertension.

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References

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