Prolonged hypertension has a ubiquitous influence on the circulation; and although its causes may vary, it is clear that its effects are far reaching. Studies by Folkow, Conway and Doyle using a variety of human and animal models showed that the increase in peripheral vascular resistance [1–3], now recognized as the hallmark of raised blood pressure (BP), was sustained by an alteration in small artery structure with a decrease in lumenal diameter and an increase in the thickness of the vascular wall, which at this level of the circulation is mainly attributable to the medial smooth muscle. This encroachment upon the lumen is not unlike the process observed in the heart, in which the thickening left ventricle (LV) impinges on the cavity only dilating when failure is imminent. Three hotly disputed areas were researched subsequently: first, was the hypertensive circulation more sensitive to vasoconstrictor stimuli? Human studies of forearm blood flow and in-vitro experiments of segments of small arteries from hypertensive patients showed that this was not so [4,5]. Second, were the structural changes a cause of the hypertension or a consequence? Once again, physiological measurements in patients pointed to the circulation changing its structure after pressure became apparent , and Bund et al.  showed that protecting the small arteries from hypertension in the spontaneously hypertensive rat prevented them from remodelling. Third, what was the exact process at work when remodelling takes place? Initially, it was assumed that as in the heart the medial layers of the artery were undergoing hypertrophy but Short  demonstrated that there was no increase in the cross-sectional area of the arterial wall in human autopsy specimens, so there could not be any hypertrophy or hyperplasia, and Korsgaard et al. [9,10] confirmed these findings and introduced the concept of eutrophic inward remodelling, in which the preexisting medial smooth muscle cells respond to increased pressure by reorientating more closely together, thereby impinging on the lumen and decreasing both the internal diameter and external circumference of the artery.
In this edition of the Journal, Agabiti Rosei and Rizzoni have taken the story further. Now, we know that eutrophic inward remodelling is the physiological response to a rising BP and designed to offset the inevitable increased wall stress that ensues . Also, the molecular processes at work are being explored, and it has been shown that hypertension upregulates αVβ3 integrin activity, which in turn increases the autophosphorylation of focal adhesion kinase (FAK) Y397 during the remodelling process . Perhaps, even more interesting is that inhibition of αVβ3 activity arrests eutrophic inward remodelling and the vascular wall responds to a rise in pressure by undergoing smooth muscle hypertrophy, which is associated with the exclusive coassociation of FAK Y397 with a different integrin β1 . This alternative response to pressure must be less advantageous and potentially important prognostically. Certainly, severe or fulminant forms of hypertension are more likely to be responsible for the earlier development of small artery hypertrophy, and target organ damage is often evident . Perhaps in support of this, Schofield et al.  examined small artery structure and myogenic function in vessel segments obtained from hypertensive type 2 diabetic patients and reported marked loss of autoregulatory activity and hypertrophy. Such patients are at increased risk of end organ damage, and the failure of myogenic tone would lead to increased wall stress and hypertrophy, but were this to be insufficient to compensate for the rise in BP, the downstream tissues would be prone to the consequences of increased blood flow.
Agabiti Rosei and Rizzoni move forward their well considered article by translating their views into the possibility that an assessment of small artery wall characteristics might be important prognostically and therefore helpful in targeting treatment to those most at risk of developing hypertension-associated complications. Certainly, Conway noted that the level of peripheral vascular resistance observed was greatest in the severest forms of hypertension and particularly so in patients with malignant phase disease in which we recognize a grim prognosis without treatment .
The Brescia Group provide longitudinal data that demonstrate for the first time that those hypertensive patients with the greatest increases in structural alteration in their small arteries had the majority of cardiovascular morbidity and mortality . Furthermore, those who had evidence of hypertrophy rather than eutrophic inward remodelling were most likely to fall into the group with the largest changes in structure . Other workers have reported similar findings . The data point to an assessment of small artery structure being prognostically more informative than even echocardiographic detection of LV hypertrophy. Therefore, if a noninvasive means of detecting vascular wall parameters could be introduced into clinical practice, we might have an important way of improving and indeed personalizing treatment for hypertension. The use of retinal scanning to view arterioles directly holds promise but would need to be able to reliably measure wall lumen ratio and cross-sectional area possibly at maximum dilatation and reproducibly to provide the technology needed. Confocal microscopy of the nailfold vasculature may be an alternative, but more work is needed. Certainly, we know that only some classes of drug reverse established structural changes, and we have no insight as to whether even they are useful once hypertrophy has begun to occur. The failure of drug therapy to reverse completely hypertension-associated cardiovascular risk might be explained by just this problem at least to some extent. Agabiti Rosei and Rizzoni are to be congratulated on opening up this area for thought at this time.
Conflicts of interest
There are no conflicts of interest.
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