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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1999  |  Volume : 10  |  Issue : 3  |  Page : 257-266
Blood Vessel Structure in Hypertension

Department of Medical Sciences, University of Edinburgh, Western General Hospital, Crewe Road South Edinburgh, Scotland, United Kingdom

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How to cite this article:
Irving R J, Walker BR. Blood Vessel Structure in Hypertension. Saudi J Kidney Dis Transpl 1999;10:257-66

How to cite this URL:
Irving R J, Walker BR. Blood Vessel Structure in Hypertension. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2022 Jan 26];10:257-66. Available from: https://www.sjkdt.org/text.asp?1999/10/3/257/37232
The vascular tree is a supremely efficient mechanical system. It takes a lifetime for the subtle increase in work required of the vasculature in hypertension to manifest itself in the catastrophic events of stroke or myocardial infarction. A myriad of physiological, hormonal and pathological abnormalities have been observed in established hypertension. This review discusses the role of alterations in the structure of blood vessels in patients with essential hypertension, with particular reference to the specialized and regulatory vasculature of the kidney. These changes will be discussed in the context of hypertension as a lifelong process with origins in fetal life.

Increased peripheral resistance with a normal cardiac output is the hallmark of hypertension. Resistance varies throughout the vascular tree and vessels of less than 500 micrometers in diameter form the greatest component. [1],[2] Abnormalities of these vessels have been described in hypertension in human skin, [3] muscle [4],[5] conjunctival, [6] retinal [7][,8] and gut vasculature [9] and could be shown to increase resistance. [10] However, in the presence of normal renal function, the effect on blood pressure from increased peripheral resistance would be nullified by pressure natriuresis. [11] In other words, over a remarkably wide range of blood pressure, any rise in pressure is followed by increased sodium excretion, which restores the original blood pressure. Transplantation experiments performed in immunologic ally compatible rats, between hypertensive and normotensive individuals show that the transplanted kidney dictates the blood pressure of the recipient. [12],[13] A series of patients with end-stage renal failure, as a result of severe hypertension, who had therapeutic renal transplantation, gained remission from hyper­tensive disease maintained over five years. [14]

This study preceded routine cyclosporin use, which confers hypertension upon most recipients. Therefore, if increased peripheral vascular resistance is a primary change in hypertension, factors involved in the generation and maintenance of increased vascular resistance must be considered for both renal and non-renal vasculature.

   Structural Changes in Peripheral Vessels Top

The vasculature of an individual with established hypertension has several distortions from normal. Vessel walls are thickened in the small arteries and resistant arterioles. Moreover, vessels are diminished in number or rarefied. These changes have been described for more than one hundred years.

Thickening of vessel walls with consequent increase in wall to lumen ratio is called hypertrophy. Schiffrin has reviewed the methods used to investigate this change in humans. [15] The term implies growth and division of wall components but this may be misleading. Baumbach and Heistad [16] were the first to suggest that it is remodeling of existing vessel components that result in the thicker wall. They demonstrated this in cerebral arteries of Stroke prone Spontaneously Hyper­tensive Rats (SpSHR). Work reviewed by Heagerty et al [17] has shown that in most studies this is the dominant effect in essential hypertensive patients and in Spontaneously Hypertensive Rats (SHR). Growth and cell division contribute much less.

Rarefaction refers to reduced vessel number per volume of tissue. This phenomenon has been demonstrated in multiple tissues in humans and rats. Short described arteriolar rarefaction in hypertensive cadavers in the 1950s. [9],[18]. In vivo rarefaction has been demonstrated, in association with hyper­tension, in conjunctivae, [6] skeletal muscle4 and nail beds. [19] This may be a response to local pressure in the studied network and a functional state may precede anatomical changes. SHR have diminished numbers of arterioles, which can be overcome by high dose vasodilators in young animals but not in older animals. [20] However, this interpretation is challenged by data from experiments9 inducing hyper-tension by coarctation. [21] The hindquarters of the animal are not exposed to the elevated systemic pressure but nevertheless rarefaction occurs. The cellular mechanism involved in development of rarefaction may well involve apoptosis. Electron micro­graphic studies demonstrated cellular markers of apoptosis [22] in endothelial tissues in Gold­blatt hypertensive rats (one kidney, one clip).

   Hemodynamic Effect of Structural Vascular Changes Top

Bjorn Folkow in Sweden performed the key experiments that first illustrated the functional significance of these changes in the 1950s. Prior to this, decreases in the minimum vascular resistance of tissues had been described in hypertensive patients with plethysmography. [23] Folkow showed for the first time [24] that the relationship between minimum vascular resistance and presser responses to noradrcnaline was identical in hypertensives and normatensives. He inferred that for any given presser tone, resistance from hypertensive vessels would be greater as a result of the increased luminal encro­achment by the thickened wall. Thus, the structural change in the vessel wall is translated into the functional change of increased resistance without requiring alterations in smooth muscle activity or pharmacological sensitivity to vasoactive agents

The "Structural Factor" Folkow described is a generally accepted principle in hyper­tension. The relative significance of rarefaction arouses more controversy. Hallback et al [25]. simulated rarefaction in the hindquarters of a rat by injection of microspheres. These were 50 pm in diameter and blocked 50% of microvessels of that size. No enhancement of the effect of vasoconstrictors was observed and he concluded that rarefaction did not significantly increase resistance. However, a mathematical model study by Greene et al[26] demonstrated that rarefaction of 42% of 3 rd or 4 th order vessels would lead to 21% increased resistance. This model was based on the hamster cheek pouch, which forms an idealized branching structure. This may have different characteristics to vascular beds that contribute more to peripheral resistance. Modeling techniques are not yet sufficiently advanced to describe interactions between hypertrophied vessels and rarefied networks. It has been suggested that vessel remodeling proximally and distal rare­faction will act in a synergistic manner [27] and the combination will lead to greater resistance than the simple product of each component. Sophisticated modeling may be the path for future research to establish the relative importance of observed changes in different vessels.

   Changes in the Renal Vessels Top

The cardinal histological change seen in hypertensive kidneys is narrowing of the afferent arteriole. The classic studies by Sommers[10] identified a spectrum of disorders throughout 1800 renal biopsies. This varied from focal spasm of arterioles with concentric overlapping of smooth muscle in the mildest cases to more severe changes with endothelial edema leading to luminal encroachment, smooth muscle hypertrophy, degenerative changes with hyalinization and irregular and focal luminal narrowing. Traditionally these changes were thought to develop after some years of established hypertension. [28] A recent study examined renal tissue from young adults who died traumatically and demonstrated a correlation between arteriolar narrowing with increasing incidence of hypertension in their country of origin. [29] These changes are not uniformly distributed through the kidney and will lead to relative ischemia in the more severely affected nephrons. Sealey [30] et al have proposed that the renin secreted by the ischemic nephrons will have a dispropo­rtionate effect on blood pressure. The majority of normal nephrons will ensure adequate renal function, and increases in blood pressure will tend to lead to correction through sodium natriuresis. However, this response will be incomplete due to the promotion of sodium retention though angiotensin II from the ischemic nephron population. This phenomenon may explain the variation between individuals responses to sodium loading, and the residual circulating renin in some hypertensive patients when renin should be suppressed by increased perfusion pressure.

The Origins of Vascular Structural Changes:

Developmental Relics or Compensatory Plasticity?

So far this review has described structural changes, which have been reported and commented on the hemodynamic alterations they produce. We have shown that vascular structure can influence renal function, peripheral vascular resistance and hence blood pressure. The second half of the review will outline a hypothetical basis for their occurrence. Recent epidemiological studies [31],[32],[33] have shown strong links between low birthweight and increased risk of hypertension. It has been proposed that events in early life permanently alter, or "program" subsequent development in favor of cardiovascular disease. These associations may be explained by distorted vascular development, consequent to the factors which impair intra-uterine growth.

Hypertrophy and rarefaction are maladaptive changes in view of the demonstrable decrease in mechanical efficiency that they cause and the vascular catastrophes that they predate, but they result from the same developmental principles that create efficient structures with minimal mechanical work. Control of vessel growth and development is deter­mined by nutritive demands from the dependant tissues. [34] Feedback from the resulting flow in the form of shear stress and wall stress alters growth and deve­lopment of cellular wall components. These processes determine embryonic development of a vascular tree and subsequent remodeling to the changing demands of the growing organism. This plasticity of vascular structure is retained in the mature adult and can be demonstrated in animal models.

The interaction between the ability of structures to remodel towards the ideal for their function, and the limits imposed by the other components of the cardiovascular system is shown in [Figure - 1], and can be illustrated by the following example.

Wall remodeling has been shown mathe­matically to reduce tension in the vessel wall when it is exposed to increased pressure [27] and is thus adaptive to the circumstances of that vessel. However remodeling results in luminal encroachment and increased resistance which increases the pressure loading on the system, and is maladaptive. This also illustrates the central idea of programming; where adaptive responses to circumstances early in life may become maladaptive for the adult organism.

We suggest that structural changes may be present at an early stage of development as a result of relative increases in flow and pressure in the growth-restricted fetus. These changes or an increased capacity to develop these changes may persist and manifest themselves in adult life as hypertension. To support our hypothesis, we will describe normal vascular development, animal experiments demonstrating retained adult plasticity and human studies showing altered vascular structure early in the development of hypertension.

   Vascular Embryology Top

Vascular cells evolve from mesoderm, differentiating into blood cellular components and vessel components before flow is established. Growth of vessel walls is initially controlled by vascular endothelial growth factor that primarily leads to differentiation and division. As marshes of blood vessel components stir into flowing channels, tissue demands mediated through oxygen and adenosine as paracrine factors stimulate further growth. [35] A combination of vessel wall factors in response to circumferential and shear stress stimulates development of additional wall components and accumulates smooth muscle cells and extracellular matrix including elastic fibers that characterize arteries and arterioles. The cellular and molecular mechanisms governing this process are beginning to be identified and are comprehensively reviewed by Cowan and Langille. [36] Network factors are less well studied in vivo than cellular mechanisms. The methods by which genetic blueprints for a vascular tree or organogenesis are translated into functioning structures are beginning to be understood. A family of homebox genes have been identified and linked to tissue polarity in wing development in Drasophila [37] and myocardial repair in rats. [38]

   Plasticity of Mature Vasculature Top

There are limits to the further differenti­ation of the mature vascular tree. Clearly it is not possible to grow a second aorta. Animal models suggest that there is consi­derable plasticity of vessels supplying muscles. Pig right ventricles hypertrophy in response to pulmonary artery banding.[39] Hemodynamic studies of the right coronary arteries in these animals demonstrated no additional resistance compared to control arteries, which indicates that the increased demands of the muscle produce an ideal mechanically minimized network. The new network has an increased ratio of arterioles to capillaries. The number of vessel divisions from coronary ostium to capillary increased from 10 to 11. The increased branching begins in proximal vessels indicating residual plasticity in well differentiated structures. Tissue demands is not the sole stimulus to vessel growth in this model and it is possible that chronic vasodilatation and muscle tension is transformed into vascular growth.

Another model that demonstrates adult vascular plasticity is the cremaster muscle of rats with unilateral orchidectomy. [40] The operated side has diminished vessel density in an identical milieu other than loss of load bearing function of the muscle.

   Mathematical Modeling Top

Mathematical models of vascular networks support the theory that shear stress and circumferential stress in combination as modifiers of growth can lead to idealised flow.[41] Alternatively with different criteria in the model, the network would remodel into a single vessel.[42] These models are relatively crude, limited to describing possible mechanisms to create capillary meshworks to supply homogenous tissue metabolic demands.

   Plasticity of Renal Vasculature Top

Irregular involvement of nephrons in pathological responses could be accentuated in the presence of limited absolute nephron number. This theory was first outlined by Brenner in 1988. [43] Nephron number varies between individuals from 300,000 to 1,100,000, [44] and is determined at birth. [43] Further renal growth is finite and limited to increasing the size of components of the nephron. Individuals with numerically limited functional reserve are more susceptible to the pathological processes of high blood pressure described above. The supporting evidence is accumulating but is circumstantial. Populations with susceptibility to salt sensitive hypertension have been shown to have smaller average size of kidneys. [45] Experimental reduction of renal mass increases the risk of hypertension [46] as does surgical reduction in removal of renal tumors [47] or unilateral nephrectomy for donation.[48]

   Programming of Vascular Structure Top

Programming of hypertension has recently become a major research area investigating key epidemiological observations linking early development with cardio­vascular mortality. Programming suggests that finite stages of development are windows of plasticity in which the limits of system responses are set. Sexual differen­tiation has been recognized for many years to depend upon a surge of male hormones to change the phenotype that would otherwise be female. However, within the last ten years numerous epidemiological studies have linked early life events to cardiovascular mortality [31],[32],[33] and have been performed in wealthy Western countries and in India.[49],[50] These studies traced adults from populations with detailed birth records and have shown correlations between low birth weight and later occurrence of hypertension. The variation in adult blood pressure is typically two mmHg per kg of birth weight[51]

The epidemiologists who have produced this work believe maternal nutrition in pregnancy to be the cause of low birth weight and subsequent hypertension.

Our recent study of 635 young adults in Edinburgh demonstrated confounding influences in this relationship from maternal blood pressure, and birth weight, which might at least partially represent a marker for an inherited influence of hypertension.[52]

   Vascular Structural Changes in Early Hypertension Top

Evidence supporting programming of vascular structure as an important process in the development of hypertension comes from studies showing structural changes early in the process, especially in people with familial tendency to develop hyper­tension. Japanese subjects with a strong family history of hypertension have diminished reactive hyperemic forearm blood flow.[53] Subjects with early essential hypertension characterized by higher cardiac output had capillary rarefaction demonstrated in conjunctival micrographs.[54]

Familial determinants of blood pressure have been studied through a novel epidemiological method. The population attending a single medical center at Ladywell in Edinburgh had their blood pressure screened. By studying groups of offspring defined by a function of their own and their parents' blood pressure, factors associating with their familial tendency to develop high blood pressure can be separated from subsequent factors upon their blood pressure. Non-invasive studies of microvascular blood flow demonstrated abnormalities in the offspring who shared above average blood pressure with their parents. [55] They had 50% lower maximal blood flow in heated skin, [Figure - 2], and diminished capillary number following venous occlusion, [Figure - 3]. These abnormalities are of the same magnitude observed in established hypertension but the differences in blood pressure between the subject groups were small (6mmHg). Thus abnormalities in the micro­vasculature are present prior to a rise in pressure, and not present in everyone with a higher pressure, suggesting a possible causative role in the inherited rise in blood pressure.

These changes will tend to increase blood flow in the fewer vessels, which will provide, as we know from the animal studies, the stimulus to develop more vessels to correct the mismatch between growth and flow. Yet the abnormalities persist. This might be due to decreased sensitivity to the stimulus of increased flow or to the growth message transuded by that flow. Alternatively the peripheral microvesel structures may be an appropriate response to the pressure set by the kidney, which may have fewer nephrons or populations of ischemic nephrons influencing the pressure natriuresis relationship. All of these mechanisms could be programmed in utero and be worth investigating as possible explanations of the epidemiological observations

Whatever the precise mechanism, we can appreciate that these subtle maladaptations can develop, persist and feedback to increase peripheral resistance. Adaptive structural alterations from the ideal may be beneficial during times of rapid growth and development, or protective during nutritional insufficiency. However, they over burden the organism with the structural basis for ongoing maladaptations and the ultimate catastrophes of stroke or myocardial infarction.

   References Top

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Correspondence Address:
R John Irving
Department of Medical Sciences, University of Edinburgh, Western General Hospital, Crewe Road South Edinburgh, Scotland, EH4 2XU
United Kingdom
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