Vascular Aging and Disease of the Small Vessels
Cardiovascular events are the consequence of vascular damage at both the macro and microcirculatory level. The relationship between large stiffening artery and microvascular disease may be bidirectional, since wave reflection from microvascular sites could increase systolic blood pressure and pulse pressure, while transmission of increased arterial pulsatility to microvessels could represent a mechanism of damage. Hypertension and aging share similar mechanisms of vascular dysfunction. In fact, vascular remodelling, endothelial dysfunction and vascular stiffness are common features in hypertension and aging. Structural and functional changes in small arteries occur during normal and accelerated aging, possibly triggered by hypertension. A cross-talk may be present between large and small artery changes, interacting with pressure wave transmission and reflection, exaggerating cardiac, brain and kidney damage, and finally leading to cardiovascular and renal complications.
KeywordsAging Elderly Hypertension Macrocirculation Microcirculation Small resistance arteries
Vascular ageing may be triggered by several mechanisms, including oxidative stress, inflammation, proliferation of smooth muscle cells, increased collagen content, etc. . These factors may be involved in specific changes in vascular structure (remodeling) and function that may be observed both in large arteries and in the small vessels.
During aging, in large, conductance arteries an increased stiffness, an increased intima media thickness and an increased lumen diameter might be observed [1, 2, 3], while in smaller vessels, an increased wall thickness, an increased lumen diameter and an increased wall cross-sectional area are more commonly detected [3, 4]. In the large arteries it was postulated that the presence of hypertension accelerates the vascular effects of aging per se . In fact, the observed increment of 2 m/s in the pulse wave velocity (index of large artery stiffness) between the age groups “50–59 years” and “more than 70 years”, in a large reference population of 11.092 subjects, is anticipated by the presence of hypertension by 10–20 years .
2 Aging and the Microcirculation
In animal models of aging an outward hypertrophic remodeling, characterized by increased lumen diameter increased wall cross-sectional area, with an unchanged tunica media to internal lumen ratio (M/L) are usually observed . In animal models of hypertension and in human hypertension, on the contrary, an inward eutrophic remodeling is observed, with a decreased lumen diameter, an increased M/L and an unchanged wall cross-sectional area [3, 6, 7, 8]. In secondary forms of hypertension, in diabetes mellitus, and, probably, also in elderly hypertensives (although in this case very few data are at present available), an inward hypertrophic remodeling is more frequently observed, with a decreased lumen diameter, an increased M/L and an increased wall cross-sectional area [3, 9, 10, 11].
3 Aging and Large Arteries in Hypertension
Arterial stiffness plays a key role in the pathophysiology of the cardiovascular system. During systole, the left ventricle increases the pressure in large vessels, that, due to their elastic properties, may store a significant part of the left ventricle ejection volume . After the closure of the aortic valve, the recoil of the large vessels to their diastolic dimensions pushes the blood towards the periphery. This mechanism allows to reconcile the intermittent contraction of the left ventricle with the permanent need of tissues for oxygen and nutriments . This phenomenon is quantitatively larger in healthy and younger subjects . Arterial compliance favors left ventricular function as it reduces left ventricular workload, and enhances diastolic perfusion, crucial to the delivery of blood to the myocardium through the coronary vessels. As the propagation of the pressure wave in elastic tubes occurs at a definite velocity, it is possible to measure arterial stiffness through the pulse wave velocity (PWV). Aortic stiffness is approached by the carotid to femoral PWV (normal values: < 10/12 m/s) [12, 14]. In addition, the pressure wave can reflect from the peripheral vasculature (branching, resistance sites, stenosis), and return towards the heart . When stiffness is high, the returned wave may add to the ejection pressure. In physiological conditions, the reflected pressure wave returns in diastole, explaining why the systolic and pulse pressures measured close to the heart (central blood pressure) is lower than at the periphery .
Age and blood pressure are the two major determinants of increased arterial stiffness [12, 16]. Molecular determinants of arterial stiffness are related to the fibrotic components of the extracellular matrix, mainly elastin, collagen and fibronectin. Increased arterial stiffness was consistently observed in conditions such as hypertension, dyslipidemia and diabetes . As blood vessels become stiffer because of age-related processes, the pulse wave is transmitted more rapidly and returns to the heart during left ventricular contraction, resulting in a greater augmentation of the central aortic systolic pressure. It is therefore possible to quantify this effect through the calculation of the augmentation index.
Alterations in the mechanical properties of large arteries have a clear pathophysiological link with clinical outcome. In addition to being a measure of the cumulative influence of identified and unidentified cardiovascular risk factors on target organ damage, changes of large artery phenotype may be causative in the pathogenesis of cardiovascular events . An expert consensus document on arterial stiffness has been previously published . In this document, more than 11 longitudinal studies have been listed demonstrating that a simple measure of aortic stiffness through carotid-femoral PWV yielded prognostic values beyond and above traditional risk factors . In addition, increased aortic augmentation index is associated with coronary artery disease . Central pressures also correlate with cardiovascular risk not only in patients with atherosclerotic disease but also in apparently healthy subjects. The late systolic augmentation of the central pressure waveform is associated with an increase in left ventricular mass index independent of age and mean blood pressure  and carotid systolic blood pressure is an independent determinant of left ventricular wall thickness. Moreover, central pressure is also more closely related than brachial pressure to other important cardiovascular intermediate end points, such as left ventricular hypertrophy  and vascular hypertrophy, extent of carotid atherosclerosis, and ascending aorta diameter .
4 Relationships Between Structural Changes in the Microcirculation and Macrocirculation
Due to the viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection is smoothed out, so that microvasculature mediates steadily the delivery of nutrients and oxygen to tissues . The disruption of this function, which occurs when alterations in microvascular structure develops in response to hypertension, leads to end-organ damage. Microvascular structure is not only the site of vascular resistance but also, probably, the origin of most of the wave reflections generating increased central systolic blood pressure in the elderly , although the proper location of a reflection site may be elusive . On the other end, increased pulsatility of conduit arteries is transmitted to small arteries and may contribute to vascular injury in the resistance vasculature .
Laurent  proposed that an impedance mismatch may be present in young normotensive subjects between proximal, conductance arteries and small vessels: proximal vessels (e.g. thoracic aorta) are elastic, while more distal vessels (e.g. muscular arteries) are stiffer; therefore reflected waves travel at a low PWV . This may have two relevant consequences: the first one is that there is a late systolic (or even diastolic) arrival of reflected waves, thus inducing a modest or negligible increase in central systolic blood pressure, which is, in fact, normal. The second consequence is that an increase stiffness of the small arteries represent a protective mechanism limiting transmission of excessive pulsatility into the distal microcirculation . In the elderly and in the hypertensive patient, there is a loss of this impedance mismatch, since proximal vessels become stiffer, and the distal muscular arteries remain stiff. Therefore, reflected pressure waves travel backward fast (increased PWV), arriving in the early systole and, therefore, increasing central systolic blood pressure . In addition, there is also more transmission of excessive pulsatility into the microcirculation, increasing microvascular and organ damage .
When the possible prognostic role of small artery remodelling in hypertension was evaluated, only the M/L of subcutaneous mall arteries and pulse pressure (a rough index of large artery stiffness) entered the model, thus suggesting that, at least in these high risk subjects, structural changes in the microcirculation and alterations on mechanical properties of large arteries are the two most important factors in predicting outcome . Possible relationships between subcutaneous small resistance artery structure, and blood pressure values were investigated in a population of more than 200 normotensive subjects and hypertensive patients . Among the most important predictors of small artery structure there were clinic systolic, diastolic and mean blood pressure, 24-h systolic and diastolic blood pressure, and the ratio between pulse pressure and stroke volume, taken as a rough index of large artery compliance.
Recently, we investigated possible relationships between indices of large arteries stiffness and the M/L of subcutaneous small resistance arteries . M/L ratio was significantly related to brachial systolic blood pressure and pulse pressure (r = 0.36 and 0.31, P < 0.01, respectively) and to central systolic and pulse pressure (r = 0.41 and 0.37, P < 0.01, respectively). A positive correlation was observed between M/L ratio and carotid-femoral pulse wave velocity (r = 0.45; P < 0.001); this correlation remained statistically significant after adjustment for age and mean blood pressure. M/L ratio was also associated to aortic augmentation index (r = 0.33; P = 0.008), and also this correlations remained statistically significant after adjustment for potential confounders.
Few years ago, a non-invasive approach for the evaluation of retinal arteriolar morphology (Scanning laser Doppler flowmetry) was proposed  and validated . The wall to lumen ratio of retinal arteries (evaluated non-invasively), is strongly correlated with the gold standard measurement of the media to lumen ratio of subcutaneous small arteries, obtained with locally invasive bioptic techniques (wire micromyography) .
Using this non-invasive approach, Ott et al.  could very recently demonstrate that central pulse pressure correlated with wall-to-lumen ratio (r = 0.302; P < 0.001), central augmentation index normalized to a heart rate of 75 beats per minute correlated with wall-to-lumen ratio (r = 0.190; P = 0.028). Multiple regression analysis revealed an independent relationship between wall to-lumen ratio and central pulse pressure (β = 0.277; P = 0.009), but not with other classical cardiovascular risk factors.
Using the same technique, it was also demonstrated that wall-to-lumen ratio of retinal arterioles was significantly related to clinic systolic (r = 0.18; P = 0.002) and pulse pressure (r = 0.20; P = 0.001), to 24-hour systolic (r = 0.25; P = 0.0001) and pulse pressure (r = 0.17; P = 0.005), and to central systolic (r = 0.16; P = 0.006) and pulse pressure (r = 0.18; P = 0.002) , as well with carotid artery stiffness, as assessed by echotracking technique .
Thus, central pulse pressure, indicative of changes in large conduit arteries is an independent determinant of vascular remodeling in retinal arterioles [26, 27]. Such a relationship indicates a coupling and crosstalk between the microvascular and macrovascular changes attributable to hypertension . In fact, increased wall:lumen ratio and rarefaction of small arteries are major factors for an increase in mean blood pressure; then the higher mean blood pressure, in turn, may increases large artery stiffness through the loading of stiffer components of the arterial wall at high blood pressure levels; finally the increased large artery stiffness may be a major determinant of the increased pulse pressure, which, in turn, damages small arteries in different organs (heart, brain, retina, kidney) and, in general, favours the development of target organ damage . Thus, the cross-talk between the small and large artery exaggerates arterial damage, following a vicious circle .
5 Small Vessels Disease and Brain Damage in Hypertension and Aging
Large artery stiffening was also demonstrated to be related to cerebral lacunar infarctions , or to large white matter hyperintensities  which are usually expression of cerebral microvascular disease. Elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain . Pulse pressure and pulse wave velocity, markers of arterial stiffness, have been associated with stroke, dementia, and lowered levels of cognitive function , and it was suggested that aggressive treatment of risk factors associated with greater arterial stiffness may help preserve cognitive function with individuals’ increasing age .
The possibility to prevent cognitive decline with aggressive blood pressure lowering treatment was recently confirmed .
Also pulsatility index was associated with lower memory scores and worse performance on tests assessing executive function. When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains . Middle cerebral artery pulsatility was also demonstrated to be the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and middle cerebral artery stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis .
Therefore, it seems that a close relationship has been established between microvascular damage in brain and kidney and indices of age and hypertension (pulse pressure, aortic pulse wave velocity, and augmentation index) . A possible pathophysiological explanation of this link can be offered on the basis of differential input impedance in the brain and kidney, compared with other systemic vascular beds: torrential flow and low resistance to flow in these organs exposes small arterial vessels to the high-pressure fluctuations that exist in the carotid, vertebral, and renal arteries. Such fluctuations, measurable as central pulse pressure, increase 3- to 4-fold with age. Exposure of small vessels to highly pulsatile pressure and flow explains microvascular damage and resulting renal insufficiency and intellectual deterioration . Therefore, the logical approach to prevention and treatment requires reduction of central pulse pressure . Because the aorta and large arteries are not directly affected by drugs, this entails reduction of wave reflection by dilation of conduit arteries elsewhere in the body . This can be accomplished by regular exercise and by drugs such as nitrates, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers . This hypothesis may account for greater and earlier vascular damage in diabetes mellitus (relative microvascular fragility) and is similar to that given for vascular changes of pulmonary hypertension caused by ventricular septal defects and other congenital vascular shunts . In summary, loss of cognitive function and hypertension are two common conditions in the elderly and both significantly contribute to loss of personal independency. Microvascular brain damage—the result of age-associated alteration in large arteries and the progressive mismatch of their cross-talk with small cerebral arteries—represents a potent risk factor for cognitive decline and for the onset of dementia in older individuals .
6 Hypertension and Aging: Recent Data in the Microvasculature
More than two decades ago, Taddei et al.  demonstrated that hypertension causes premature aging of endothelial function in humans. In normal subjects, the response to intra-arterial administration of acetylcholine in the forearm, in terms of forearm blood flow, declined with age, but this decline was anticipated in patients with hypertension. Thus, the endothelial dysfunction that occurs in hypertension seems to represent an accelerated form of vascular impairment that occurs in aging .
However, a very relevant question regards whether a similar behaviour is also present when the structure of small resistance vessels is taken into account.
Recently the relationships between microvascular structure and function and age were investigated both in normotensive subjects and in hypertensive patients .
There is hardly any doubt that cardiovascular events are the consequence of vascular damage at both the macro- and the microcirculatory level. The relationship between large stiffening artery and microvascular disease may be bidirectional, since wave reflection from microvascular sites could increase systolic blood pressure and pulse pressure, while transmission of increased arterial pulsatility to microvessels could represent a mechanism of damage. Hypertension and aging share similar mechanisms of vascular dysfunction . Vascular remodelling, endothelial dysfunction and vascular stiffness are common features in hypertension and aging .
Structural and functional changes in small arteries occur during normal and accelerated aging triggered by hypertension . A cross-talk may be present between large and small artery changes, interacting with pressure wave transmission, exaggerating cardiac, brain and kidney damage, and finally leading to cardiovascular and renal complications .
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Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 2.Weber T, Segers P. Changes in central hemodynamics, wave reflection, and heart-vessel coupling with normal and accelerated aging. In: Nilsson P, Olsen MH, Laurent S (eds) Early vascular aging (EVA): new directions in cardiovascular protection. pp 83–95, 2015.Google Scholar
- 3.Laurent S, Agabiti-Rosei E. The cross-talk between the macro- and the microcirculation. In: Nilsson P, Olsen MH, Laurent S (eds) Early vascular aging (EVA): new directions in cardiovascular protection. pp 105–118, 2015.Google Scholar
- 4.Laurent S, Rizzoni D. Targeting central blood pressure through the micro-and macrocirculation cross-talk. In: Nilsson P, Olsen MH, Laurent S (eds) Early vascular aging (EVA): new directions in cardiovascular protection. pp 297–306, 2015.Google Scholar
- 8.Aalkjaer C, Eiskjaer H, Mulvany MJ, Jespersen B, Kjaer T, Sorensen SS, Pedersen EB. Abnormal structure and function of isolated subcutaneous resistance vessels from essential hypertensive patients despite antihypertensive treatment. J Hypertens. 1989;7:305–10.Google Scholar
- 11.Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, Girelli A, Rodella L, Bianchi R, Sleiman I, Agabiti Rosei E. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non insulin dependent diabetes mellitus. Circulation. 2001;103:1238–44.CrossRefGoogle Scholar
- 14.Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H, On behalf of the European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588–605.CrossRefGoogle Scholar
- 17.Weber T, Wassertheurer S, Schmidt-Trucksäss A, Rodilla E, Ablasser C, Jankowski P, Lorenza Muiesan M, Giannattasio C, Mang C, Wilkinson I, Kellermair J, Hametner B, Pascual JM, Zweiker R, Czarnecka D, Paini A, Salvetti M, Maloberti A, McEniery C. Relationship between 24-h ambulatory central systolic blood pressure and left ventricular mass: a prospective multicenter study. Hypertension. 2017;70:1157–64.CrossRefGoogle Scholar
- 23.Muiesan ML, Salvetti M, Rizzoni D, Paini A, Agabiti-Rosei C, Aggiusti C, Bertacchini F, Stassaldi D, Gavazzi A, Porteri E, De Ciuceis C, Agabiti-Rosei E. Pulsatile hemodynamics and microcirculation: evidence for a close relationship in hypertensive patients. Hypertension. 2013;61:130–6.CrossRefGoogle Scholar
- 35.SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK, Cleveland ML, Coker LH, Crowe MG, Cushman WC, Cutler JA, Davatzikos C, Desiderio L, Erus G, Fine LJ, Gaussoin SA, Harris D, Hsieh MK, Johnson KC, Kimmel PL, Tamura MK, Launer LJ, Lerner AJ, Lewis CE, Martindale-Adams J, Moy CS, Nasrallah IM, Nichols LO, Oparil S, Ogrocki PK, Rahman M, Rapp SR, Reboussin DM, Rocco MV, Sachs BC, Sink KM, Still CH, Supiano MA, Snyder JK, Wadley VG, Walker J, Weiner DE, Whelton PK, Wilson VM, Woolard N, Wright JT Jr, Wright CB. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321:553–61.CrossRefGoogle Scholar
- 36.Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson Ó, Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age. Gene/Environment Susceptibility-Reykjavik study. Brain. 2011;134(Pt 11):3398–407.CrossRefGoogle Scholar
- 41.De Ciuceis C, Rossini C, Agabiti Rosei C, Sarkar A, Porteri E, La Boria E, Gavazzi A, Petroboni B, Pileri P, Agabiti Rosei E, Rizzoni D. Relationship between age and structural alterations in subcutaneous small resistance arteries in hypertensive patients. In: 25th European meeting on Hypertension and cardiovascular protection (ESH) 2015, Milan, 12–15 June, e100 (7D.03), 2015.Google Scholar
- 43.Bruno RM, Grassi G, Seravalle G, Savoia C, Rizzoni D, Virdis A, Study Group on Micro- and Macrocirculation of the Italian Society of Hypertension (SIIA). Age- and sex-specific reference values for media/lumen ratio in small arteries and relationship with risk factors. Hypertension. 2018;71:1193–200.CrossRefGoogle Scholar