The burden of vascular disease in diabetes and hypertension: from micro- to macrovasculardisease –
the “bad loop”



by H. A. J. Struijker-Boudier, The Netherlands


Harry A. J. STRUIJKERBOUDIER,
PhD
Dept of Pharmacology
and Toxicology
Maastricht University
Maastricht
THE NETHERLANDS

Hypertension and diabetes often coexist in the elderly population. Both are risk factors for atherosclerotic disease. Furthermore, they affect the same target organs—heart, brain, and kidney—causing subsequent cardiovascular morbidity and mortality. Target organ damage is mostly due to an effect on the arterial tree. The arterial tree consists of three compartments with important structural and functional differences. The most proximal part contains elastic arteries with a diameter >2 mm. The more distal arterial compartment contains muscular arteries with a diameter of 150 μm to 2 mm. The third compartment is the microcirculation, with arterioles ranging from 8 to 150 μm. Both hypertensive and diabetic patients have increased large artery stiffness. In hypertension, increased blood pressure per se increases arterial stiffness. Moreover, changes in the extracellular matrix contribute to the increased stiffness. In diabetics, endothelial dysfunction is an important pathogenic mechanism and vascular effects of advanced glycation end products (AGEs) also contribute. Remodeling of the structure of the small arteries is a common feature of hypertension and diabetes. In hypertension, eutrophic inward remodeling is the major change, in contrast with hypertrophic remodeling in diabetes. With regard to microcirculation, microvascular rarefaction is the major vascular event in hypertension and diabetes. Hypertension and diabetes are characterized by a vascular syndrome that can be described as a “bad loop.” This “bad loop” starts with microvascular damage, which causes capillary and small arteriolar rarefaction. This leads to increased arterial wave reflections in the macrocirculation, which cause increased large artery stiffness and increased pulse pressure. The latter causes further damage to the microcirculation, thus reinforcing the “bad loop.”

Medicographia. 2009;31:251-256 (see French abstract on page 256)

Hypertension and diabetes are well-defined risk factors for atherosclerosis. Furthermore, both hypertension and diabetes affect the same target organs— heart, brain, and kidney—with subsequent cardiovascular morbidity and mortality. Clinically, hypertension and diabetes often occur together, with approximately 80% of diabetics also being hypertensive.1 A common denominator of the pathogenic mechanisms in hypertension and diabetes is the vascular tree. Both hypertension and diabetes affect the vascular tree at various levels. The aim of this contribution is to review the major changes in vascular function and structure in hypertensive and diabetic patients and to provide a hypothesis on the common causes of both diseases.

The various segments of the vascular tree

Although the veins are an important site for the control of body fluid volumes and cardiac output, the major focus of this contribution is on the arterial and capillary segments of the vascular tree. The arterial tree consists of three segments (Figure 1). The most proximal part contains elastic arteries with a diameter >2 mm. The more distal arterial compartment contains muscular arteries with a diameter of 150 ìm to 2 mm. The third compartment is the microcirculation, with arterioles ranging from 8 to 150 ìm.

Figure 1
Figure 1. The three segments of the arterial tree.

The basic architecture of arteries is usually described in terms of the cross-sectional arrangement of cells and extracellular matrix. The latter consists, within the media, of lamellae of elastic material with intervening layers of vascular smooth muscle (VSM) cells, collagen fibers, and ground substance.2 However, the distribution of elastin and collagen varies markedly along the longitudinal aortic axis.3 In the proximal part of the aorta, elastin is the predominant component, whereas in the distal aorta and its side branches, the collagen-to-elastin ratio is reversed, with a predominance of collagen in peripheral muscular arteries. The transition occurs rapidly over the distal 5 cm of the thoracic aorta above the diaphragm and over a similar distance in the branches leaving the arch of the aorta. Thereafter, VSM cells largely predominate. In the microcirculation, one or more layers of VSM cells and an endothelial cell layer form the arteriolar wall. Thus, it is anatomically justified to divide the arterial tree into three compartments. During development, VSM cell layers of different embryonic origin clearly reflect the differences in anatomic location.4 In the avian abdominal aorta and small muscular arteries, the smooth muscle cells are of mesodermal origin, whereas those of the aortic arch and thoracic aorta are mainly derived from the ectodermal cardiac neural crest.5 The participation of VSM cells of ectodermal origin is essential in the formation and organization of elastic laminae and tensoreceptors in the great vessels.5 These changes in VSM cells as a function of distance from the heart have been further confirmed by studies of the chemical properties, pharmacological sensitivities, and gene expression patterns of elastin and collagen along the aorta.6,7 VSM cells in the microcirculation have a different origin. The formation of microvascular networks is the result of a complex process of angiogenesis which takes place during embryogenesis, but also, thereafter, under circumstances of hypoxia, viz, tissue ischemia.8 Furthermore, recent data indicate that newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.9 Differences in origin may explain why certain classes of vasodilators (for instance, calcium channel blockers or á-adrenoceptor antagonists) act differently on proximal VSM cells compared to more distally located VSM cells.

The characteristics and amounts of elastin and collagen are to a large degree determined at a very young developmental stage and, thereafter, remain quite stable because of a very low turnover. Nevertheless, the proportion of elastin and of collagen type I and type III differs markedly between various species and has a substantially differential mechanical effect on stiffness and distensibility of the vessel wall.10 In addition, several neurohormonal factors, particularly those related to the angiotensin II and aldosterone systems, may modulate collagen accumulation.11 Collagen may also be subjected to important chemical modifications, such as breakdown, crosslinking or glycation, resulting in marked changes in stiffness.12 Finally, in central conduit arteries, large amounts of collagen are observed in the adventitia, thus contributing to altered arterial mechanical properties. Collagen is principally responsible for the discontinuities of the vessel wall, mainly at vessel bifurcations. It greatly modifies arterial rigidity and the transit of wave reflections, thereby increasing thoracic aorta pulse pressure (PP). In turn, the increased cyclic stress causes fragmentation and fracture of elastin and also causes calcification, particularly in the elderly.

Extracellular matrix is responsible for the passive mechanical properties of the arteries, particularly in the aorta and its main branches. In a cylindrical vessel, when the transmural pressure rises, a curvilinear pressure-diameter curve ensues, primarily caused by the effects of elastin at low pressure and recruitment of collagen fibers at high pressure.3,13 Nevertheless, other molecules, through their role in cell-cell and cellmatrix attachments, may contribute to the three-dimensional repartition of mechanical forces within the arterial wall.14-18 An illustrative example is given by the role of the different connexin (Cx) isotypes along the aortic axis. In rat proximal elastic arteries, the main smooth muscle cell type consists of desminnegative cells with high levels of Cx43, whereas in small to medium muscular arteries, the main cell type is desmin-positive cells, with low levels of Cx43.15 In mice lacking desmin, isobaric carotid stiffness is increased in association with enhanced vessel wall viscosity.16 In rat models, an increased sodium diet is associated with increased isobaric systemic stiffness and reduced aortic proteoglycans.17 On the other hand, chronic aldosterone excess produces increased isobaric carotid stiffness and arterial fibronectin, a process reversed by the aldosterone antagonist eplerenone.18

Finally, VSM cells do not represent a homogenous population. For the same genomic background, they may have different mixtures of phenotypes, not only with contractile and synthetic, but also with proliferative and apoptotic behavior.12,19 The relative occurrence of each of the phenotypes depends not only on age, but also on location in the vascular tree and prevailing (pathological) conditions. Contractile properties, which are mainly expressed in the distal arterial compartment, are responsible for the active mechanical properties of conduit vessels.3 Changes in VSM tone may occur either directly or through signals arising from endothelial cells. The endothelium is a source of substances, particularly nitric oxide (NO), and of signal transduction mechanisms that influence the biophysical properties of conduit arteries. NO is the principal mediator, dilating larger arteries more than smaller arteries.3,13 Whereas the role of flow- and endothelium-dependent dilation is not restricted to a particular vessel category, the role of mediators arising from the endothelium predominates in muscular distal arteries.20,21 In such vessels, the site and the pattern of wave reflections22 are influenced by the local differential effects of NO and vasoconstrictive (ie, noradrenaline, angiotensin, and endothelin) compounds.21 Research that relates arterial stiffness, the reflectance properties of the arterial system, and VSM tone is just emerging and may greatly contribute to our knowledge on the mechanisms of (systolic) hypertension.

Large arteries in hypertension and diabetes

Both hypertensive and diabetic patients have an increased stiffness of their large arteries. There is abundant evidence for increased arterial stiffness in hypertension. The reader is referred to a recent excellent volume of the Handbook of Hypertension23 for a detailed discussion of many studies that have been performed in this field. Even in the early stage of hypertension, there is evidence for reduced large artery compliance.24-27 In children, this hemodynamic pattern is frequently associated with being overweight and changes in wave reflections.28,29 Reduced arterial compliance in established hypertension cannot be attributed entirely to elevated blood pressure. Both increased smooth muscle tone and a changed wave reflection have been held responsible for reduced arterial compliance.23 Using local echotracking techniques, several authors have shown that reduced compliance is confined to central arteries (thoracic and abdominal aorta and carotid artery). In muscular arteries (brachial, radial, and femoral arteries), normal values were observed.30,31 With aging, the increase in systolic blood pressure is more pronounced than in diastolic pressure. This is caused by a reduction of arterial compliance in older hypertensive subjects.

Changes of arterial stiffness in diabetes have been reviewed by Stehouwer and Ferreira.32 Recent studies investigating the association between both type 1 and type 2 diabetes and arterial stiffness have consistently shown that these patients have stiffer arteries than nondiabetic subjects. In both groups of patients, arterial stiffness precedes clinical cardiovascular disease. In type 1 diabetes, increased pulse pressure, a common marker of arterial stiffness and determinant of cardiovascular complications in adults older than 50 years, is already present in patients in their early thirties.32 In type 2 diabetes, macrovascular changes also begin at the prediabetic stage.32 These data support the concept that diabetes, in part, has a vascular etiology.

Several mechanisms have been implicated in the diabetes-associated increase in arterial stiffness. A recent study showed that glycemia was the major determinant of arterial stiffness in diabetic patients. 33 Hyperglycemia is a notorious cause of endothelial dysfunction. Many studies have consistently shown impaired dilatation in response to endothelium-dependent agonists in diabetics.34,35 It has been suggested that the mechanism of endothelial dysfunction is based on increased inactivation of nitric oxide by either oxygen-derived free radicals or advanced glycation end products (AGEs).

An alternative or additional mechanism of large artery stiffness in diabetes is the AGE-related stiffening of collagen in the vessel wall. Evidence for such a mechanism has been derived from studies with drugs that interfere with the formation of these glycosylated vessel wall molecules.23

Microcirculation in hypertension and diabetes

At the level of small arteries, there are similarities, but also differences between hypertensive and diabetic subjects. In both pathologies, small arteries remodel. The majority of available data indicate that, in patients with essential hypertension, small arteries show a greater media thickness and a reduced lumen and external diameter (with an increased media-to-lumen ratio), without any significant change in the total amount of wall tissue.36 Therefore, the major part of the structural changes observed in these patients is the consequence of inward eutrophic remodeling without net cell growth. Recent data suggest that chronic vasoconstriction may lead to eutrophic remodeling.37,38 In addition, it has been suggested that vascular wall components move relative to each other through a process which may be integrin-mediated.39,40

In diabetic patients, a clear increase in the media cross-sectional area in small vessels has been observed, suggesting the presence of hypertrophic remodeling.41,42 This hypertrophy may be related to a cellular growth response to increased levels of insulin or insulin-like growth factor 1.41 An alternative explanation has been put forward by Schofield et al.43 These authors propose increased wall stress resulting from impaired myogenic response of the small arteries in diabetes as a possible stimulus for hypertrophic remodeling. Finally, diabetic patients show alterations of the vascular extracellular matrix, as suggested by the observation of an increased collagento- elastin ratio in their small arteries. The increased collagen deposition in the vessel wall may be due to the inflammatory and profibrotic properties of several hormones that are active in diabetics.

A final vascular site of damage in hypertension and diabetes are the small arterioles and capillaries. Vascular resistance is not only determined by the arteriolar diameter, but also by the number of perfused vessels. Microvascular rarefaction may be the result of closure of the small arterioles (functional rarefaction) or structural rarefaction, where the vessels are actually missing. Microvascular rarefaction has been a consistent observation over many years in hypertensive patients and animal models.44 In most vascular beds, not all microvessels are perfused at any one time; the fraction of nonperfused vessels constitutes a reserve that may be called upon under conditions of high metabolic demand. Progressive nonperfusion can lead to structural loss of vessels, analogous to the progression of active vasoconstriction in structural remodeling of small arteries, as discussed before.

Histological analysis of skeletal muscle biopsy samples reveals capillary rarefaction in subjects with type 2 diabetes.45 Histological capillary density is inversely related to fasting plasma glucose and fasting insulin levels and is positively related to insulin sensitivity in nondiabetic individuals.46 Microvascular permeability to large molecules, such as albumin, is increased in diabetes, a process that is linked to hyperglycemia and oxidative stress.47

Microvascular rarefaction has been consistently reported in the myocardium of hypertensives and diabetics. The functional consequence is a reduced coronary flow reserve. Reduced maximal blood flow is probably related to structural abnormalities in the coronary microcirculation, although functional factors, including endothelial dysfunction, may also contribute.48

The bad loop

The evidence discussed above suggests that hypertension and diabetes share at least two pathogenic mechanisms: decreased microcirculatory tissue perfusion and increased large artery stiffness. We recently proposed that impaired tissue perfusion underlies much of the tissue and organ dysfunction associated with chronic conditions, including hypertension, diabetes, and obesity.44 Figure 2 summarizes how the various segments of the vascular system interact to create a vicious cycle. In healthy individuals, this loop is not active. During aging, the loop may become progressively active, thus explaining the high incidence of hypertension and diabetes in the elderly. Once the loop becomes active, it slowly progresses, unless drugs or diets are given to interfere. The ideal drug or diet should target both the macro- and microvascular abnormalities in this vascular syndrome.

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Keywords: microcirculation; macrocirculation; large arteries; arterioles; capillary rarefaction; vascular disease; hypertension; diabetes