Canadian Journal of Cardiology 36 (2020) 648e658
Review
How Structure, Mechanics, and Function of the Vasculature
Contribute to Blood Pressure Elevation in Hypertension
Ernesto L. Schiffrin, MD, PhD
Lady Davis Institute for Medical Research and Department of Medicine, Sir Mortimer B. DaviseJewish General Hospital, McGill University, Montre al, Que bec, Canada
ABSTRACT
Large conduit arteries and the microcirculation participate in the
mechanisms of elevation of blood pressure (BP). Large vessels play
roles predominantly in older subjects, with stiffening progressing after
middle age leading to increases in systolic BP found in most humans
with aging. Systolic BP elevation and increased pulsatility penetrate
deeper into the distal vasculature, leading to microcirculatory injury,
remodelling, and associated endothelial dysfunction. The result is
target organ damage in the heart, brain, and kidney. In younger in-
dividuals genetically predisposed to high BP, increased salt intake or
other exogenous or endogenous risk factors for hypertension, including
overweight and excess alcohol intake, lead to enhanced sympathetic
Increased peripheral resistance is the hallmark of primary
(previously called essential) hypertension.1 Increases in pe-
ripheral resistance result from changes in either large conduit
arteries, such as the aorta and its major branches, or in
resistance vessels, which comprise the microcirculation,
including small arteries, arterioles, capillaries, and venules.
Large arteries become stiffer with aging, resulting in elevated
systolic blood pressure (BP).2 Small arteries have lumen di-
ameters of 100-300 mm or less when relaxed, and arterioles
< 100 mm, and typically have only 1 or 2 smooth muscle
layers. Small arteries and arterioles constitute the major site of
resistance to flow, generating w70% of peripheral resistance.3
According to Poiseuille’s law, resistance varies inversely with
the fourth power of the blood vessel radius. Accordingly, small
decreases in the lumen will result in large increases in resis-
tance to flow. Further downstream of arterioles, capillaries and
venules may also participate in peripheral resistance through a
process called rarefaction, whereby density of terminal arteri-
oles, capillaries, and venules in tissues is reduced.4 It has been
suggested that rarefaction may contribute to BP elevation by
raising peripheral resistance by 15%.4
Received for publication October 31, 2019. Accepted February 3, 2020.
Corresponding author: Dr Ernesto L. Schiffrin, Sir Mortimer B. Davise
Jewish General Hospital, #B-127, 3755 Côte-Ste-Catherine Rd, Montreal,
Quebec, Canada H3T 1E2. Tel.: þ1-514-340-7538; fax: þ1-514-340-7539.
E-mail: ernesto.schiffrin@mcgill.ca
See page 654 for disclosure information.
https://doi.org/10.1016/j.cjca.2020.02.003
0828-282X/Ó 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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RESUM 
E
Les grosses artères conductrices et la microcirculation participent aux
me canismes d’ele
vation de la pression arte
rielle (PA). Le rôle des gros
vaisseaux est particulièrement important chez les sujets plus âge s, le
durcissement des artères qui survient à partir d’un certain âge et qui
mène à la hausse de la PA systolique est observe  chez presque tous
les humains en vieillissant. L’augmentation de la PA systolique et de la
 se re
pulsatilite percute jusque dans les vaisseaux distaux, où elle
entraîne des lesions microcirculatoires et un remodelage qui provo-
quent à leur tour une dysfonction de l’endothe lium vasculaire. Il en
sulte des le
re sions aux organes cibles que sont le cœur, le cerveau et
les reins. Chez les sujets plus jeunes ayant une pre disposition
Structure and Mechanics of Large Conduit
Arteries and Their Effect on Blood Pressure
Blood pressure rises with aging, especially after the age of
45 years in men and w 5-10 years later in women, often
after menopause. This rise predominantly affects systolic BP,
whereas diastolic BP decreases. Cardiovascular risk seems to
be mainly associated with the rise of systolic BP.5 There has
been a suggestion that lower diastolic BP, especially < 70
mm Hg, is associated with increased risk of decreased cor-
onary flow leading to myocardial ischemia (J-curve),
particularly in patients with coronary artery disease.6 How-
ever, the enhanced risk of lower diastolic BP has been
recently attributed to age5,7 and higher systolic BP.5 These
BP changes with aging are the result of vascular remodelling,
mainly of large elastic arteries. Conduit elastic arteries, such
as the aorta and its large elastic branches, of individuals
beyond 45-55 years of age develop a process of arterioscle-
rosis of the media that leads to progressive stiffening of the
vessel wall with aging. They increasingly develop outward
hypertrophic remodelling, as elasticity is altered by the effect
of rising intravascular pressure, and degeneration and frag-
mentation of elastic fibres. As a result, elastic large vessels
stiffen and their ability to distend during systole is pro-
gressively reduced as the forward pulse wave advances along
the aorta,8 resulting in increased systolic BP. As pulse-wave
velocity accelerates because of the stiffened vascular wall,
reflected waves9 generated at points of changing impedance
arrive back earlier to the proximal aorta in late systole rather
than in diastole, augmenting systolic BP. This augmentation
Ernesto L. Schiffrin
Role of Vasculature in BP Elevation
activity and vasoconstriction. Enhanced vasoconstrictor responses and
myogenic tone become persistent when embedded in an increased
extracellular matrix, resulting in remodelling of resistance arteries with
a narrowed lumen and increased media-lumen ratio. Stimulation of
the renin-angiotensin-aldosterone and endothelin systems and in-
flammatory and immune activation, to which gut microbiome dysbio-
sis may contribute as a result of salt intake, also participate in the
injury and remodelling of the microcirculation and endothelial
dysfunction. Inflammation of perivascular fat and loss of anti-
contractile factors play roles as well in microvessel remodelling.
Exaggerated myogenic tone leads to closure of terminal arterioles,
collapse of capillaries and venules, functional rarefaction, and even-
tually to anatomic rarefaction, compromising tissue perfusion. The
remodelling of the microcirculation raises resistance to flow, and
accordingly raises BP in a feedback process that over years results in
stiffening of conduit arteries and systo-diastolic or predominantly sys-
tolic hypertension and, more rarely, predominantly diastolic hyperten-
sion. Thus, at different stages of life and the evolution of hypertension,
large vessels and the microcirculation interact to contribute to BP
elevation.
of systolic pressure partly erases the amplification of systolic
BP normally found distally from aorta to peripheral arteries,
including the brachial artery, and the difference between
peripheral and central pressure is reduced. As large vessels
stiffen and wave reflection sites move distally, the increased
pulsatility of large vessels penetrates deeper into the vascu-
lature, inducing endothelial injury and remodelling of small
vessels.8 Thus, it is likely that even when hypertension is
predominantly systolic, resistance vessels contribute to BP
elevation as well as impairment of tissue perfusion and
nutrient exchange. This results in microvascular damage in
the coronary circulation, the brain, and the kidney as well as
in the peripheral circulation of the limbs. For the changes in
the microcirculation occurring as a consequence of large
artery stiffening, and which affect nutrition and oxygenation
of tissues and arrival of mediators and elimination of waste
products of metabolism, see the discussion below.
Microcirculation
The vascular changes in the microcirculation involve re-
ductions in lumen size that may be structural, mechanical, and
functional, which lead to increased energy dissipation and
resistance to flow in small arteries and arterioles. Structural
changes in small arteries with increased media-lumen ratio
correlate with forearm minimal vascular resistance, providing a
functional significance to these changes.10 As well, there is
rarefaction with a decreased number of open terminal arteri-
oles, capillaries, and venules. All these changes contribute to
raise peripheral resistance, leading to progressive elevation
of BP.
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649
ge ne
tique à l’hypertension arte rielle, un grand apport en sel ou d’au-
tres facteurs de risque d’hypertension exogènes ou endogènes, y
compris un surplus de poids et une consommation excessive d’alcool,
accroissent l’activite sympathique et la vasoconstriction. L’augmenta-
tion de la re ponse vasoconstrictive et du tonus myoge nique devient
persistante lorsque la matrice extracellulaire s’accroît, ce qui entraîne
un remodelage des artères de re sistance dont la lumière est re tre
cie et
le rapport me dia-lumière, accru. La stimulation du système re nine-
angiotensine-aldoste rone et du système endothe line ainsi que l’acti-
vation des me canismes inflammatoires et immunitaires auxquelles la
dysbiose intestinale provoque e par l’apport en sel pourrait contribuer,
interviennent aussi dans l’atteinte et le remodelage des micro-
vaisseaux et la dysfonction de l’endothe lium vasculaire. L’in-
flammation dans le tissu adipeux pe rivasculaire et la diminution de ses
proprietes anticontractiles jouent aussi un rôle dans le remodelage des
microvaisseaux. Un tonus myoge nique exage re entraîne la fermeture
des arte rioles terminales, l’effondrement des capillaires et des vei-
nules, une rare faction fonctionnelle et enfin une rare faction anato-
mique, ce qui compromet la perfusion des tissus. Le remodelage des
microvaisseaux accroît la re sistance à la circulation, et conse quem-
ment la PA; au fil des ans, ce processus de re troaction entraîne le
durcissement des artères conductrices et une hypertension systolo-
diastolique ou essentiellement systolique et, plus rarement, une hy-
pertension essentiellement diastolique. Ainsi, à diffe rentes etapes de
la vie et de l’e volution de l’hypertension, l’interaction entre les gros
vaisseaux et la microcirculation contribue à l’e levation de la pression
arterielle.
Structure of Resistance Arteries in
Hypertension
The remodelling in hypertension of the structure of resis-
tance (small) arteries, which are arteries of 100-300 mm
diameter, may take one of 2 forms: eutrophic remodelling or
hypertrophic remodelling (Fig. 1).11,12 Eutrophic remodelling
involves a decrease in lumen diameter and outer diameter of
small arteries, with conservation or decrease of the cross-
sectional area of the media of the vessel and increase of the
media-lumen ratio. Eutrophic remodelling is found in resis-
tance arteries of rodent models of hypertension with an acti-
vated renin angiotensin-aldosterone system, such as 2-kidney
1-clip Goldblatt hypertensive rats13 and spontaneously hy-
pertensive rats (SHRs).14-17 Eutrophic remodelling is also
characteristic of small arteries of humans with stage 1 primary
hypertension.18-21 Hypertrophic remodelling, on the other
hand, is characterized by an increase of the cross-sectional area
of the media and a narrowed lumen as a result of encroach-
ment of the thickened media on the lumen, with increased
media-lumen ratio. Hypertrophic remodelling is found in
rodent models with severe hypertension, such as 1-kidney 1-
clip Goldblatt hypertensive rats,21 deoxycorticosterone ace-
tate (DOCA)esalt hypertensive rats,22 and Dahl salt-sensitive
hypertensive rats,23 in all of which the endothelin system is
activated, which may contribute to the growth of the media
both at the level of smooth muscle cells or through expansion
of the extracellular matrix.24 In humans, hypertrophic
remodelling has been described in renovascular hypertension
and pheochromocytoma,25 in primary aldosteronism,26 and in
hypertension associated with acromegaly27 and Cushing syn-
drome.28 “Remodelling” and “growth” indices can be used to
approximate the relative contribution of eutrophic and
650
Normotensive Hypertensive
Hypertrophic
Remodeling
Media/lumen
CSA
( endothelin)
Eutrophic
Remodelling
Media/lumen
= CSA
(angiotensin II)
Figure 1. Schematic drawing depicting eutrophic remodelling and
hypertrophic remodelling of resistance arteries in hypertension and
potential agents playing roles in determining the nature of remodel-
ling. As hypertension progresses, it is possible, but unproven, that
eutrophic remodelling may evolve toward hypertrophic remodelling
under the combined influence of angiotensin II and endothelin-1, other
growth factors, inflammatory and immune mechanisms, the sympa-
thetic nervous system, and high blood pressure itself. Reproduced
from Schiffrin12 with permission from Oxford University Press.
hypertrophic remodelling when varying degrees of one or the
other is found to be present.29,30 Large arterioles (lumen
diameter 20-100 mm) undergo remodelling similarly to small
arteries.29
Rarefaction of the Microcirculation and Its
Effect on Blood Pressure
The density of smaller terminal arterioles, capillaries, and
small venules is reduced in many tissues in hypertension. This
reduction in vessel density is called rarefaction, which is
another mechanism that increases peripheral resistance,
contributing w15% of the rise in vascular resistance found in
hypertension.4 Rarefaction is initially transient and functional,
resulting from enhanced myogenic tone, vasoconstriction, and
active collapse of the microvessels with obliteration of the
lumen. With progression of hypertension, rarefaction becomes
permanent and anatomic, with reduced arteriolar and capillary
density, as described in different rodent hypertensive models
of hypertension, such as 1-kidney 1-clip hypertensive rats,31
2-kidney one-clip rats,32 DOCA-salt hypertensive rats,33
SHRs,34 and Dahl salt-sensitive rats,35 and in human
hypertension.36
Interestingly, rarefaction may be an early change in human
hypertension. Early studies have demonstrated an initial phase
of hyperdynamic circulation in young adults with borderline
hypertension.37,38 Associated with this stage of early border-
line hypertension, several studies have reported the presence of
rarefaction in humans.39 Rarefaction in humans with estab-
lished hypertension had already been reported by Short in a
very early autopsy study.40 The possible sequence of these
changes may be increased sympathetic activity due to a higher
set point of BP, what Stevo Julius has termed “the higher
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Canadian Journal of Cardiology
Volume 36 2020
BPeseeking behaviour of the central nervous system,”41
leading to an increase in cardiac output and a hyperdynamic
circulation.37,38 However, this later evolves into established
hypertension associated with elevated peripheral resistance.
The transition occurs as remodelling of small arteries and
arterioles and microcirculatory rarefaction increase peripheral
vascular resistance over the course of hypertension as a result
of enhanced myogenic tone and vascular reactivity and
eventual remodelling of the resistance circulation as discussed
below, causing sympathetic tone to decrease.
Mechanisms of Remodelling of the Vascular
System
An important question that needs to be answered is
whether the phenotype of resistance arteries in hypertension is
a consequence of hemodynamic, endocrine, inflammatory and
immune, paracrine, or autocrine factors present, activation by
BP elevation, or a primary genetically determined abnormality
leading to the molecular, cellular, structural, and functional
characteristic vascular changes found in hypertension. This
will be only summarily discussed, because it is addressed in
other manuscripts in this compendium. Hemodynamic effects
and the role of the sympathetic nervous system, especially in
borderline hypertension, have already been discussed, and the
mechanism whereby increased perfusion pressure results in
remodelling of the resistance vessels and microcirculation is
addressed below. The renin-angiotensin-aldosterone system
plays a role in remodelling in experimental and genetic hy-
pertension in rodents42,43 and in humans,20,44,45 in the latter
as demonstrated in studies using blockers of these systems.
The role of the endothelin (ET) system in BP elevation and
remodelling of small arteries was first demonstrated by the
enhanced expression of ET in the endothelium of ET-1 in
DOCA-salt46 and aldosterone-induced hypertension,43 as well
as in 1-kidney 1-clip Goldblatt hypertension.47 Furthermore,
ET antagonists lowered BP and corrected vascular remodelling
in mineralocorticoid hypertension in rodents.48 However,
SHRs did not exhibit overexpression of ET in the vascula-
ture46 and did not respond to ET antagonists with BP
lowering or correction of vascular remodelling.49 The role of
ET-1 has been extended by our demonstration of microcir-
culatory remodelling and endothelial dysfunction occurring
with transgenic overexpression of human ET-1 in endothe-
lium in mice, either congenitally24 or inducibly.50,51
Furthermore, overexpression of ET-1 in endothelium of
small arteries was shown in stage 2 hypertension in humans.52
We and others have also demonstrated a role for inflam-
mation and immunity in the processes leading to remodelling
of the vasculature in rodent models contributing to BP
elevation. Macrophages, which are part of the innate immune
system, were shown to be critical for angiotensin IIeinduced
small artery remodelling, endothelial dysfunction, and BP
elevation.53,54 T-effector lymphocyte deficiency is associated
with reduced vascular remodelling and BP elevation in mice
infused with angiotensin II.55 On the other hand, adoptive
transfer of T-regulatory lymphocytes, which are antiin-
flammatory through production of interleukin (IL) 10 and
transforming growth factor (TGF) b lowers BP, corrects
endothelial dysfunction in mice receiving angiotensin II,56
and corrects vascular remodelling in mice infused with
Ernesto L. Schiffrin
Role of Vasculature in BP Elevation
aldosterone.57 gd T cells, which are unconventional innate-
like lymphocytes that can produce interferon-g and IL-17,
also have been show to play a role in BP elevation, small ar-
tery remodelling, and endothelial dysfunction in mice infused
with angiotensin II and in BP regulation in a human cohort.58
Salt may contribute to activation of the immune system,
specifically TH17 lymphocytes in the intestinal wall, via
changes in the gut microbiome,59 leading to enhanced low-
grade inflammation that contributes to BP elevation and
vascular injury. The inflammatory response may affect peri-
vascular fat, normally a source of anticontractile agents,
including adiponectin, leading to enhanced vasoconstriction
and vascular remodelling.60,61
The genes participating in the induction of the vascular
changes associated with hypertension are in the process of
being identified with the use of genome-wide association
studies as well as candidate gene approaches. Many relate to
the vasculature and particularly to the endothelium.62,63
MicroRNAs, small noncoding RNAs of w20 base pairs that
regulate gene expression, may be important in the remodelling
of small arteries. We recently investigated microRNAs
expressed in resistance arteries of angiotensin IIeinfused mice
to determine whether they could contribute to modulation of
BP and vascular remodelling.64 We identified, with the use of
an unbiased approach (microRNA and mRNA sequencing
with molecular interaction analysis), a microRNAe
transcription factor coregulatory network involved in
vascular injury in mice made hypertensive by means of 14-day
angiotensin II infusion. A candidate gene approach identified
up-regulated miR-431-5p encoded in the conserved 12qF1
(14q32 in humans) miRNA cluster, whose expression corre-
lated with BP, and which is up-regulated in human athero-
sclerosis. Gain- and loss-of-function in human vascular
smooth muscle cells demonstrated that miR-431-5p regulates
gene expression in part by targeting Ets homologous factor.
In vivo, miR-431-5p knockdown delayed angiotensin IIe
induced BP elevation and reduced vascular remodelling in
mice, which confirmed its potential role in hypertension and
vascular injury.
In eutrophic remodelling, the vascular wall is restructured
with smooth muscle cells aligned more closely to encircle the
lumen without any change in the volume of the media or the
stiffness of the vessel wall. A combination of growth and
apoptosis,65-67 the latter in the periphery of the artery wall,
could lead to the reduced outer diameter of the vessel, with
inward growth encroaching on the lumen and reducing its
diameter. Changes in extracellular matrix components and
adhesion molecules could result in rearrangement of smooth
muscle cells and restructuring of the vascular wall found in
these vessels.68 The vasoconstricted state due to the increased
myogenic tone becomes embedded in the newly deposited
extracellular matrix in the media and adventitia consisting of
collagen and fibronectin, with characteristic remodelling of
the vessel wall. Integrins link components of the extracellular
matrix and the cytoskeleton and play roles in signal trans-
duction. We have proposed that changes in these anchorage
sites are involved in the rearrangement of smooth muscle cells
in remodelled small arteries in hypertension and could be
involved in the persistently narrowed lumen and embedding
of the vasoconstricted state of small arteries via enhancement
of cell-matrix attachments and changes in their distribution on
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651
the surface of smooth muscle cells. In arteries of SHRs,
expression of avb3 and a5b1 integrins in mesenteric arteries
increase as they reach adulthood together with increases in the
volume density of collagen.69 Alpha5 integrins and fibro-
nectin, which is their ligand, have been reported by other
authors as well to be increased in the aorta of SHRs.70
Hypertrophic remodelling is associated with growth of the
media with narrowing of the lumen. Increased smooth muscle
cell number71,72 and volume73,74 are also present, with
increased collagen and fibronectin deposition. Extracellular
matrix glycoproteins colocalize with proliferating smooth
muscle cells and could play a role in the proliferative response.
Fibronectin75 and osteopontin76 can modulate hypertrophic
remodelling. Osteopontin is an arginine-glycine-aspartate
(RGD)econtaining protein that adheres to vascular smooth
muscle cells through avb3 integrins77 and is associated with
the synthetic smooth muscle cell phenotype found in the
vascular wall,78 contributing to extracellular matrix deposi-
tion, a major component of the remodelling of blood vessels
in hypertension.68,69,79-82
Both eutrophic and hypertrophic remodelling are influ-
enced by agents such as angiotensin II, whose actions are
enhanced in hypertension.20,73 Angiotensin II stimulates the
deposition of both fibrillar and nonfibrillar components of the
extracellular matrix.83,84 Nonfibrillar matrix components
include proteoglycans that carry glycosaminoglycans synthe-
sized by vascular smooth muscle cells in response to growth
factors,85 which modulate proliferation and differentiation86
and whose synthesis is increased in the vasculature of
SHRs.87 Collagen types I and III are the major constituents of
the intima, media, and adventitia and are also found together
with collagen types IV and V on endothelial and smooth
muscle cell basement membranes.88-90
What are the mechanisms for increased abundance of
extracellular matrix proteins in resistance arteries in hyper-
tension? Beyond the effect of increased biosynthesis of extra-
cellular matrix components, the activity of matrix
metalloproteinases (MMPs), including MMP-1 and MMP-3,
is reduced in the serum of SHRs90,91 and in human primary
hypertension.92,93 Thus, enhanced synthesis of collagen type I
is not counterbalanced by collagen degradation by MMPs. In
the aorta and mesenteric arteries of stroke-prone SHRs, gene
expression of collagen types I, III, and IV was up-regulated.
MMP-1 and MMP-3 activity was decreased in the mesen-
teric arterial bed of young SHRs before hypertension became
established, leading to the progressive accumulation of fibro-
nectin and proteoglycans found later in adult SHRs.85,87 In
adult SHRs, the activities of proeMMP-2 and activated
MMP-2 were reduced in mesenteric arteries, facilitating
accumulation of collagen types IV and V and fibronectin.94-96
MMP inhibition has been shown to prevent elastin degener-
ation, collagen deposition, and increases in BP by means of its
effects on the monocyte chemotactic peptide 1/TGF-b1/ET-1
proinflammatory signalling axis.97
Mechanical Abnormalities of Resistance
Arteries That Influence Blood Pressure
The stiffness of the artery wall is increased in rodent
models of hypertension and in humans with primary hyper-
tension. This change may increase resistance to blood flow by
652
reducing the distensibility of the vessel wall during systole.
The stiffness of mesenteric resistance arteries in SHRs may be
reduced initially,98,99 followed later by increased stiffness of
wall components, with reduced distensibility as collagen
deposition is enhanced.68 Large second-order cerebral small
arteries from stroke-prone SHRs were stiffer than vessels from
WKY rats, whereas smaller third-order arteries exhibited
decreased stiffness.29,98 In Dahl salt-sensitive rats100 and in
DOCA-salt hypertensive rats,101 small artery stiffness was not
enhanced. In humans, progressive arterial stiffening was found
as individuals age or develop hypertension.102 Subcutaneous
small arteries from hypertensive patients exhibited normal
stiffness compared with vessels from normotensive individuals
in some studies,103 whereas decreased stiffness was reported in
others.104 The latter finding seemed to be age-related, because
other groups of older subjects showed no difference in the
stiffness between vessels of hypertensive and normotensive
individuals.81,103 We have proposed that early in the disease,
collagen fibres may be recruited at higher distending pressures
in small arteries from patients with stage 1 hypertension than
in vessels from normotensive subjects, whereas later, compli-
ance of resistance arteries in hypertensive individuals may be
reduced in part owing to the smaller lumen and greater
collagen-elastin ratio, and the engagement of collagen fibres
and resulting tensing of the collagen jacket at earlier portions
of the pressure curve.104 In fact, decreased wall stiffness was
demonstrated in cerebral arterioles from stroke-prone
SHRs,98,105,106 which could be attributed to increased
elastin content.107 In peripheral resistance arteries, vessel wall
stiffness was increased in SHRs with increased volume density
of collagen or collagen-elastin ratio.68,80 In subjects with
primary hypertension in whom we showed vascular stiffness to
be initially decreased despite an increased collagen-elastin
ratio,81 proteoglycans could be responsible for some of the
changes in stiffness of resistance arteries. Interactions between
extracellular matrix proteins, smooth muscle cells, and adhe-
sion molecules may be critical for cell attachment to fibrillar
components of the extracellular matrix and may regulate the
degree of stiffening, explaining differences reported in the
literature.
Functional Abnormalities of Resistance Arteries
in Hypertension
Abnormal resistance artery function in hypertension may
increase peripheral resistance by reducing lumen diameter
owing to enhanced constriction. Early in experimental hy-
pertension, enhanced myogenic tone107 and increased
response to norepinephrine have been reported.14,15,17
Impaired endothelium-dependent relaxation has been a
functional abnormality considered to be prototypical of hy-
pertension, although not always present, especially in early
hypertension.104 It can also contribute to stiffening and
vasoconstriction, including at the level of large arteries.108 A
reduction in acetylcholine-induced and flow-mediated vaso-
dilation has been repeatedly reported in rodent and human
resistance arteries,104,109-111 and thus reduced vasodilation
could contribute to BP elevation. Vasoconstriction has clas-
sically been described as a mechanism for the increases in
vascular tone in hypertension,112 in both human vessels17
and experimental hypertensive rodents.14 Interestingly,
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Canadian Journal of Cardiology
Volume 36 2020
vasoconstrictors such as ET-1 and vasopressin, and even
norepinephrine, often induce reduced vasoconstriction
compared with normotensive control subjects,3,18 indicating
that the enhancement in vasoconstriction in hypertension may
reflect the effects of the Laplace’s law, whereby amplification
of vasoconstrictor responses is caused by structural or me-
chanical reduction of lumen diameter.113-116 Some in-
vestigators have argued against a structurally based exaggerated
vasoconstriction,117,118 which has been contradicted by
others.119 Augmented vasoconstriction has also been reported
in responses to angiotensin II in human blood vessels.3,18
Reactive oxygen species production by smooth muscle cells
from resistance arteries of hypertensive humans is enhanced in
response to angiotensin II, and this may relate to coupling of
the AT1 angiotensin receptor to signalling events with
increased calcium entry and release in smooth muscle cells
from vessels from experimental animals and humans with
hypertension120-123 and could contribute to the inflammatory
response described above.
The extracellular matrix may participate in the mechanisms
of abnormal function of resistance arteries in hypertension.
Peptides carrying the minimal integrin-binding RGD
sequence induce rapid endothelium-dependent and slower
endothelium-independent relaxation of rat aortic rings,
mediated by binding to avb3 integrins124,125 via reduction of
intracellular calcium in vascular smooth muscle cells,126
mediated by Kþ channels127 or L-type Ca2þ-channels, the
latter also by binding to a5b1 integrins.128 RGD-containing
peptides may also cause endothelium-dependent vasocon-
striction mediated by ET-1 in rat skeletal muscle arterioles.129
Contraction of smooth muscle has been demonstrated to in-
crease proportionally to amounts of fibronectin that it is in
contact with,130 indicating that when fibronectin70 or the
fibronectin receptor a5b1 integrin69 are increased, occupancy
of the latter may increase contractility and vascular resistance.
Inhibition of vascular MMP-2 in rat mesenteric arteries has
demonstrated the vasoconstrictor effects of big ET-1, which
arises from MMP-2emediated cleavage to release the vaso-
constrictor peptide ET-1[1-32].131
Natural history off HTN according to the Framingham
Fra Study:
Role of the vasculature
Prehypertension ISH
Small artery remodeling (preHTN) → reflected waves → ↑SBP → ISH
IDH SDH
Small artery remodeling (IDH) → reflected waves → ↑SBP → SDH
ISH SDH
↑SBP → Small artery remodeling → SDH
Figure 2. Natural history of hypertension (HTN) according to the Fra-
mingham Study.132 The risk of different subtypes of hypertension
evolving into other subtypes and the potential role that the vascular
phenotype may contribute to this evolution, thus determining the
natural history of these different subtypes, are depicted. IDH, isolated
diastolic hypertension; ISH, isolated systolic hypertension; SBP, sys-
tolic blood pressure; SDH, systo-diastolic hypertension. Reproduced
from Schiffrin2 with permission from Elsevier.
Ernesto L. Schiffrin 653
Role of Vasculature in BP Elevation

Salt Central nervous system Renin-angiotensin system Endothelin system

Genes

Sympathetic nervous system

Catecholamines
Aldosterone
Damage-activated
molecular patterns?

Inflammation Oxidative stress

Immune system activation

Cardiac output Cardiac output

Cytokines
Chemokines Vasoconstrictor responses
Myogenic tone
Endothelial dysfunction and vasodilatation
Smooth muscle proliferation and vascular remodeling
Collagen and fibronectin Vascular stiffening
Microbiome ␣v␤3 integrins, glycosaminoglycans
dysbiosis Matrix metalloproteinases
Rarefaction of terminal arterioles and capillaries

Large artery stiffness Systolic BP

Pulsatile energy to the periphery
Resistance to blood flow Diastolic BP

End-organ damage

Hypertension Stroke
Myocardial infarction
Heart failure
Chronic kidney disease

Figure 3. Summary diagram of different mechanisms contributing to remodelling of the vasculature and its role in blood pressure elevation. BP,
blood pressure.

Relation of the Vascular Phenotype to
Evolution of Different Subtypes of Hypertension
(Natural History of Hypertension)
Evaluation of the Framingham Study findings have pro-
vided novel views of the natural history of hypertension132
and potentially of the contribution of blood vessels to
different stages of hypertension or elevation of BP and pres-
ence of different phenotypes. Using data from the cohort
studied from 1955 to 1965, the risk of developing different
subtypes of hypertension (prehypertension, isolated systolic
hypertension, isolated diastolic hypertension, and systo-
diastolic hypertension) after 10 years was compared with the
group with optimal BP (< 120/80 mm Hg). Interestingly,
this evolution occurred when drug therapy was mostly un-
available. Subjects with normal BP (between 120/80 mm Hg
and 130/85 mm Hg) had similar risks of developing isolated
diastolic hypertension (> 3-fold), isolated systolic
hypertension (> 3-fold), and systo-diastolic hypertension
(> 3-fold). Subjects with high-normal BP (between 130/85
mm Hg and 140/90 mm Hg) were 8 times more likely than
those with optimal BP to develop systo-diastolic hypertension,
and 5 times more likely to develop isolated systolic hyper-
tension. Their relative risk of developing isolated diastolic
hypertension was low, however. Accordingly, pre-
hypertension, as defined by 7th Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure, had elevated risk of
evolving toward both systo-diastolic hypertension and isolated
systolic hypertension. We have proposed that small degrees of
BP elevation could lead to changes in timing of wave reflec-
tion because of altered impedance in remodelled small arteries.
Reflected waves returning proximally earlier could result in
systolic augmentation.2 As the conduit vessels stiffen due to
the systolic BP elevation with increased collagen or

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654
calcification, Windkessel function of these vessels is lost.
Thus, proximal large arteries can store more energy during
systole and recoil during diastole, resulting in higher central
systolic pressure, lower central diastolic pressure, increased
pulse pressure and isolated systolic hypertension (Fig. 2).
Subjects with isolated diastolic hypertension at baseline
were mostly male obese smokers and therefore at high car-
diovascular risk. Thus, isolated diastolic hypertension is not
benign. Isolated diastolic hypertension patients had a 23-fold
higher risk than subjects with optimal BP of developing systo-
diastolic hypertension. Severe small artery remodelling in
subjects with isolated diastolic hypertension could lead as well
through early wave reflection to augmentation of pulse pres-
sure and isolated systolic hypertension.
Subjects with isolated systolic hypertension at baseline
were at 7-fold higher high risk of developing systo-diastolic
hypertension than optimal BP subjects. Large-artery stiffening
through increased pulsatility penetrating deep into the
microcirculation could result in small-artery injury and
remodelling (Fig. 2), raising diastolic BP. Indeed, the media-
lumen ratio of small arteries correlated with pulse pressure in
elderly hypertensive subjects with a mean age of 70 years.133
We have shown similar results in hypertensive patients with
a mean age of 55 years.134 Also, in a cohort of hypertensive
patients investigated by Mitchell et al.,135 aortic pulsatility
correlated with forearm vascular resistance. This suggests an
interaction between large arteries and the microcirculation,
with increased pulsatility transmitted downstream eliciting
potentially endothelial dysfunction and reduced vasodilation,
enhanced vasoconstriction through myogenic tone, and small-
artery remodelling. The latter, through changes in impedance
resulting from remodelling, could accelerate reflected wave
return, worsening large-artery stiffening and increasing pulse
pressure.136
Does Vascular Remodelling of Large or Small
Arteries and the Microcirculation Contribute to
the Development of Elevated Blood Pressure in
Primary Hypertension?
The preceding paragraph describes how different subtypes
of hypertension may evolve from prehypertension, and one
into another, and their potential relationship with the vascu-
lature. One additional aspect is the role of baseline aortic
diameter. Data from different cohorts has suggested an initi-
ating role for a small aortic diameter in subjects at risk of
developing hypertension.137 This could be followed by
increased stiffness of conduit arteries, contributing as well to
the lower diastolic BP associated with aging. In younger in-
dividuals, does small-artery remodelling through increased
peripheral resistance contribute to elevated diastolic BP? Mi-
nor BP elevations induced by increased sympathetic activity
and increased cardiac output could lead to endothelial
dysfunction, decreased vasodilation, increased myogenic tone,
and small-artery remodelling. The latter, through an ampli-
fying effect on BP, could then feed back into a vicious circle
that slowly over many years nonlinearly results in progressive
BP rise. However, stopping antihypertensive medication in
experimental animals has been associated with a more rapid
rise in BP in those animals in which vascular remodelling had
been corrected.138 Cross-transplantation experiments in
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Canadian Journal of Cardiology
Volume 36 2020
angiotensin II-1a receptoredeficient mice have shown that
the angiotensin II-1a receptor in the kidney and in extrarenal
tissues, including the systemic vasculature, plays a role in BP
elevation,139 strongly suggesting a role for peripheral small
arteries in hypertension. In humans, correction of remodelling
of the vasculature has accompanied lowering of BP. These
variables are difficult to dissociate, although beta-blockers,
particularly atenolol, may lower BP without improvement of
blood vessel structure or function,20 whereas renin-
angiotensin blockade both lowers BP and corrects remodel-
ling of small arteries.20,44 A cause-effect relationship remains.
however, difficult to establish unambiguously. Notwith-
standing these questions about the role of blood vessels in BP
elevation, correcting the vascular phenotype early in the dis-
ease could allow preventing incident hypertension140 or the
increasing severity of BP elevation and its complications.
Conclusion
Endothelial or smooth muscle cell changes, adhesion
molecules, and extracellular matrix components contribute to
molecular, structural, mechanical, and functional changes that
characterize the vascular phenotype in hypertension, resulting
in stiffening of large arteries, reduced lumen size of small ar-
teries and arterioles, and rarefaction of terminal arterioles,
capillaries, and venules, leading to increased peripheral resis-
tance, the hallmark of primary hypertension. As a result, tissue
nutrition, mediator access, gas exchanges, and removal of
waste products are compromised, contributing to target organ
damage. A cross-talk between stiffening of large conduit ar-
teries and remodelling of small resistance vessels (Fig. 2)
contributes to progressive increases in resistance to flow and
elevation of BP, triggered by activation of the sympathetic
nervous system, the renin-angiotensin-aldosterone system, the
ET system, and other vasoactive agents, with an inflammatory
and immune component associated with salt-induced gut
microbiome dysbiosis that together leads to the vascular
changes found in hypertension (Fig. 3).
Funding Sources
The author’s work was supported by Canadian Institutes of
Health Research (CIHR) First Pilot Foundation Grant
143348 and a Canada Research Chair (CRC) on Hyperten-
sion and Vascular Research from the CRC Government of
Canada/CIHR Program.
Disclosures
The author has no conflicts of interest to disclose.
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