Journal of Human Hypertension (2009) 23, 773–782
& 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00
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REVIEW
Angiogenesis and hypertension: an update
R Humar, L Zimmerli and E Battegay
Division and Research Unit of Internal Medicine, University Hospital, Zurich, Switzerland
The purpose of this review is to provide a basic
understanding of the important relationship between
microvascular remodelling, angiogenesis and hypertension, that is, provide an overview of recent experimental and clinical evidence from anti-hypertensive
and pro- and anti-angiogenic therapy with respect to
hypertension and microvascular structure. Microvascular rarefaction, that is, a loss of terminal arterioles
and capillaries, is found in most forms of human and
experimental arterial hypertension. This further increases peripheral resistance, and aggravates hypertension and hypertension-induced target organ damage.
In some cases with a genetic predisposition, hypertension is preceded by a loss of microvessels. Therefore,
new therapies aimed at reversing microvascular rarefaction potentially represent candidate treatments of
hypertension. The microvasculature is formed by the
continuous balance between de novo angiogenesis and
microvascular regression. Imbalanced angiogenesis, in
addition to functional shut-off of blood flow, contributes
to microvascular rarefaction. Numerous clinical trials
assessing anti-angiogenic agents in cancer patients
show that this therapy leads to microvascular rarefaction and causes or aggravates hypertension. The
development of specific pro-angiogenic treatment to
correct hypertension or ischaemic disorders, however, it
is still in its infancy. On the other hand, long-term
treatment by classic anti-hypertensive therapies that
present vasodilator activity can correct for hypertension-associated rarefaction in man.
Journal of Human Hypertension (2009) 23, 773–782;
doi:10.1038/jhh.2009.63; published online 13 August 2009
Keywords: angiogenesis; vascular rarefaction; vascular peripheral resistance; endothelial dysfunction
Introduction
Blood vessels are capable of structural alteration
over time in addition to the acute changes in tone.
Restructuring includes an increase in vascular
mass—vessel wall thickening, enlargement or dilation—and alteration in capillary density, that is
microvascular rarefaction. Angiogenesis and vascular remodelling represent two aspects of a series of
events that determine the structure and arrangement
of vascular beds: the angiogenic process gives rise to
new microvessels and the remodelling process leads
to structural changes in the vessel or the loss of
microvasculature.
Microcirculation has an important role in the
pathophysiology of hypertension. Peripheral resistance is determined primarily by small arteries
(150–300 mm diameter) and arterioles (10–150 mm
diameter). The disappearance of capillaries and
pre-capillary arterioles, a phenomenon known as
microvascular (capillary) rarefaction, is a hallmark
of hypertension. During hypertension capillary
endothelium loses function, microvessels become
constricted and unperfused and eventually disappear. Also, impaired angiogenesis leads to an
Correspondence: Professor E Battegay, Division of Internal
Medicine, University Hospital, Zurich CH-8091, Switzerland.
E-mail: [email protected]
Received 10 March 2009; revised 10 June 2009; accepted 30 June
2009; published online 13 August 2009
underdeveloped microcirculatory system during
development in the first place and predispose to
hypertension in later life.
Microvascular rarefaction increases peripheral
resistance in the microcirculation, thereby reducing
blood flow and reserve and further elevating blood
pressure. These are major contributing factors to
the clinical complications of hypertension, such
as myocardial ischaemia, stroke and end-organ
damage. This cycle is well documented in several
animal models of hypertension. In humans, capillary rarefaction has been demonstrated in essential
hypertension and genetically predisposed individuals by using in vivo capillaroscopy of the nail fold
and skin microvasculature, and by displaying
changes in the retinal microvasculature. Several
areas of research have led to new insights into the
interactions between microvascular rarefaction and
hypertension.
Microvessels contribute to vascular
peripheral resistance
In 1989, Greene et al.1 quantitatively estimated the
relative contribution of arteriolar rarefaction and
arteriolar constriction to the increase in total
peripheral resistance and changes in patterns of
flow distribution that are observed in hypertension.
A mathematical model of the hamster cheek pouch
intraluminal microcirculation was constructed, and
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then rarefaction and constriction of third-order and
fourth-order arterioles were performed separately on
the model. Results were quantified on the basis of
the changes in the computed vascular resistance.
The maximum increases in resistance in the
model runs were 21% for rarefaction and 75% for
constriction. Rarefaction, but not constriction, had a
major effect on the degree of heterogeneity in blood
flow in various vessel orders. These results demonstrated that, at least hypothetically, vessel rarefaction significantly influences tissue blood flow
resistance to a degree that is comparable to vessel
constriction. Moreover, unlike constriction, microvascular rarefaction markedly altered blood flow
distribution.1
The small diameter of microvessels particularly
affects flow resistance, which increases by the
fourth power when the diameter decreases, as
described for slow viscous flow by the Hagen–
Poiseuille law. However, investigations in small
microvessels under physiological conditions in vivo
revealed an unexpectedly high flow resistance; flow
resistance in 10-m microvessels at normal haematocrit exceeded flow resistance in a glass tube of
corresponding diameter approximately four times.2
This increase may be related to interactions between
blood components and the inner vessel surface,
which might increase local viscosity or create
turbulent flows.2 Up to 30% of total peripheral flow
resistance is generated while passing the microvasculature as compared with 45–50% when blood
passes terminal arteries and arterioles.
Capillary endothelial cells may contribute to
capillary constriction.3,4 Many vasoactive chemicals
induce reorganization of the endothelial microfilament system and cell surface area. Ischaemia
reperfusion causes focal narrowing along the capillaries, which is consistent with constriction. In
isolated rat hearts, this reduction in capillary
diameter is blocked by preventing F-actin re-polymerization by phalloidin.5 This implies that the
contractile properties of microvascular endothelial
cells may also potentially contribute to the regulation of blood pressure.5
All of this information together indicates that
microvessels do contribute to peripheral resistance
because of high flow resistance and microvascular
rarefaction, and possibly also because of microvessel
contractility.
The microvasculature is rarefied in
hypertension
After hypertension develops, microvascular rarefaction emerges or worsens over a short time interval.
For example, rats that are made hypertensive
through surgical reduction of renal mass and
the administration of a high salt intake develop
endothelial damage, followed by rarefaction within
3 days.6 The primary structural alterations in these
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microvessels appear to involve a loss of vessel
integrity due to dissociation of the endothelial and
smooth muscle components of the arteriolar wall.6
In patients with essential hypertension, also structural disappearance rather than functional shutting
of microvessels reduces the density of capillaries in
the skin of the dorsum of the fingers.7,8 Vice versa,
we may detect functional, but not structural capillary rarefaction in patients with mild blood pressure
elevation.9
Microvascular rarefaction can be a primary event10
because remodelling of resistance arteries and
microvessels can be totally11–13 or partially14 independent of blood pressure. Patients with borderline
essential hypertension have skin capillary densities
that are as low or even lower than those in patients
with established hypertension.15 Moreover, impaired
microvascular vasodilatation and capillary rarefaction are associated with a familial predisposition to
essential hypertension.16 Normotensive offspring of
individuals with essential hypertension have fewer
capillaries on the dorsum of their fingers.17 Therefore, impaired angiogenesis during development or
early in life might predispose to high blood pressure.16 In addition, deficient embryonic vascular
development, low birth weight18 and impaired
postembryonic vascular growth impede the formation of microvascular networks.19,20 Thus, capillary
rarefaction mostly predates, but can also follow
sustained hypertension (Figure 1).
Mircovascular rarefaction also emerges with senescence. Ageing is accompanied by impaired
Figure 1 Hypertension and vascular rarefaction, a vicious circle
that could be interrupted by pro-angiogenesis. Increased and
untreated blood pressure harms microvessels, leads to the
destruction of capillaries and accelerates the pathogenic effects
of vascular rarefaction. A reduced capillary count may be
genetically predetermined or a consequence of a low birth weight.
This vascular rarefaction increases peripheral resistance and
eventually contributes to the development of hypertension.
This vicious circle could be terminated by the stabilization of
vascular homeostasis and growth of new microvessels through
pro-angiogenic or long-term anti-hypertensive therapy by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.
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R Humar et al
775
angiogenesis due to deficient expression of several
angiogenic growth factors and receptors as demonstrated by experiments in animal models21,22–25,26
(Figure 1). The clinical consequences are detrimental during revascularization of ischaemic heart
disease and during the repair of injured tissues.27
A causative link between decreased angiogenic
potential and a higher incidence of hypertension in the aged population still needs to be
demonstrated.
Microvascular densitiy during developing hypertension has been well documented in several animal
models and tissues.28–31 However, not all tissues
displayed reduced microvascular densities: larger
microvascular networks that were occasionally
found in the mesenterium of spontaneously hypertensive rats (SHR) displayed higher vessel density as
compared with similar areas in normotensive control animals.31 Hypothetically, these hypertensive
microvascular networks in the rat mesentery are
hypersensitive to angiogenic stimuli, whereas an
overall perturbation of angiogenesis would lead to
rarefaction in remaining tissue of the same animal.31
In an earlier study in hypertensive patients, no
changes were found in capillary number in the
quadriceps muscle.32 Thus, the full understanding
of the microcirculation’s role in hypertension requires a continued characterization of microvascular
architectures in different tissues, and during the
time course of developing hypertension.31
However, it is technically more difficult to
demonstrate microvascular network formation in
humans in developing hypertension. The structure
of small arteries in humans is studied by biopsies
taken from subcutaneous fat.33,34 Capillary rarefaction in humans is studied by capillaroscopy of the
nail fold microvasculature in vivo.7,10,15 Microvascular rarefaction and disadvantageous branching
geometry,35,36 and a narrower arteriolar caliber37–39
are also found in the retinal microcirculation of
hypertensive patients. These retinal microvascular
structures in humans may be analyzed more frequently, with precision and non-invasively during
developing hypertension in the future because of
recent advances in retinal photography and morphometric analysis.39
Endothelial dysfunction is associated
with microvascular rarefaction
Besides perturbed angiogenesis, also the balance in
endothelial production of vasodilating and vasoconstricting mediators is altered in hypertension. This
imbalance results in an apparent decrease in
endothelium-dependent relaxations and is termed
‘endothelial dysfunction’. Endothelium-dependent
relaxations are impaired in hypertensive patients
and in animal models of hypertension.40 The
endothelial dysfunction that is observed in hypertension appears to be a consequence of high blood
pressure because a variety of anti-hypertensive
treatments normalize these responses. Therefore,
endothelial dysfunction in hypertension is sometimes specified as ‘secondary’.40 Reduced bioavailability of nitric oxide (NO) and accordingly, an
impairment of endothelial NO-dependent vasodilation, appears to be the key process through which
endothelial dysfunction is manifested.41
Nitric oxide formation is also a prerequisite for
angiogenesis to occur (for specific review see Luque
Contreras et al.42). A strong local vasodilation
precedes the outgrowth of endothelial sprouts and
marks the first steps of angiogenesis.43 The absence
of the NO pathway (either as a result of pharmacological inhibition or gene disruption of endothelial
NO synthase (eNOS) prevents ischemia-,44 portal
hypertension-45 or bFGF-46,47 induced angiogenesis.
Furthermore, decreased levels of endothelial NO
synthase and inducible NOS inhibit neovascularization in animal experiments thatuse sponge implants
in young versus aged mice48 or in myocardial angiogenesis in vitro.49 Ischaemia-induced angiogenesis
is generally impaired in cardiovascular diseases
associated with decreased NO synthesis.42 In line,
exogenous supplementation of NO by NO-donors
restores ischaemia-induced angiogenesis in in vivo
and in vitro models.44,50
Thus, endothelial dysfunction in hypertension
may contribute to decreased angiogenic capacity
of capillaries because of an impairment of NO bioavailability.42,46
Anti-angiogenic therapies can cause
hypertension
Angiogenesis does not initiate malignancy but
promotes it, such as in tumour progression and
metastasis. Many angiogenesis inhibitors that target
newly forming microvessels in tumours are currently in clinical trials of all phases. At present,
inhibitors of the vascular endothelial growth factor
(VEGF) pathway are the most clinically advanced;
bevacizumab, a humanized variant of a murine antiVEGF-A monoclonal antibody, is the only approved
anti-angiogenic treatment for cancer therapy to date.
Paracrine signalling through the VEGF receptor-2
pathway is essential for developmental and pathological angiogenesis, and its role in the formation and
maintenance of blood vessels, tumour development
and metastasis has been studied extensively.51–53
Endogenous VEGF produced by endothelial cells
is also crucial for vascular homeostasis.54 Thus,
existing microvessels may be harmed by therapeutics that target VEGF also, which might result
in vascular rarefaction and, consequently, hypertension in subjects with no predisposition to
hypertension. Indeed, several angiogenesis inhibitors have now been implicated in the development
of hypertension.55–57 A meta-analysis of randomized
controlled trials of patients with cancer that were
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R Humar et al
776
treated with bevacizumab (1850 patients from seven
trials) revealed a significant dose-dependent increase in risk of hypertension.58 In early studies
with bevacizumab, hypertension was seen in 22% of
cases, compared with 8% in control groups. Stage 3
hypertension was seen in 11% of the bevacizumabtreated cohort.59
In a recent study in 20 patients, bevacizumab
treatment-induced hypertension was accompanied
by endothelial dysfunction and capillary rarefaction; both changes are closely associated with and
could be responsible for the rise in blood pressure
that was observed in most patients.60 Bevacizumab
targeted not only the pathological and ‘switched’
vessels feeding the tumour area, but also the
‘normal’ arterioles and capillaries far from the
tumour zone in patients from that study.60 Similarly,
Telatinib, a multi-growth factor kinase inhibitor,
caused hypertension, microvascular rarefaction and
changed microvascular characteristics in patients
with advanced solid tumours in a recent clinical
phase-I trial.61 However, whether the observed
rarefaction is structural (capillaries not present) or
functional (that is, presence of nonperfused existing
capillaries) is unclear.
It remains uncertain whether the changes in
response to anti-angiogenic therapy in microvessel
architecture are reversible. Still, after cessation of
anti-angiogenic therapy, blood pressure usually
normalizes60 or is controllable with angiotensinconverting enzyme inhibitors (ACE-I) and in more
severe cases, calcium channel blockers medication.62,63
More recently, vascular destabilizing agents are
being tested, which act preferentially on the mature
tumour vasculature. These agents cause a rapid
stasis of blood flow in the tumour core after its
administration.64 Here, the inherent differences
between tumour blood vessels and the blood vessels
that are associated with normal tissue make the
tumour vasculature a unique target.64,65 A tumourvasculature-selective treatment of malignant disease
may possibly avoid hypertension as an adverse
effect.
Thus, inhibiting angiogenesis is a promising
strategy for the treatment of cancer and other
disorders, including age-related macular degeneration. An additional insight gained is that antiangiogenic therapy leads to microvascular rarefaction and causes or aggravates hypertension
(Figure 1).
Pro-angiogenesis might reduce the
development of hypertension
Angiogenesis counterbalances rarefaction in hypertension is (Figure 1). During angiogenesis, preexisting cells proliferate and migrate to form a new
vessel in response to angiogenic molecules and
hypoxia that results from tissue injury.
Journal of Human Hypertension
Therapeutic angiogenesis, that is, promoting new
vessel growth to treat ischaemic disorders is important for virtually all strategies to re-grow or
engineer new tissue and is an exciting frontier of
cardiovascular medicine. However, pro-angiogenic
therapy is still in its infancy.
None of the larger placebo-controlled trials, where
single angiogenic growth factors were tested in
patients with myocardial or limb ischaemia, have
yielded convincing positive results so far.66,67 Overall, suboptimal delivery and incorrect targeting may
have led to these disappointing results.68 Single
growth-factor therapy leading to induction of
mature, persistent and functional vessels in vivo
works only when its release is precisely timed.69
This can be achieved by the incorporation of
angiogenic molecules into carrier devices, such as
natural or synthetic polymers or timed release of the
triggers by implantable minipumps.70 Likewise, an
intervention that controlled the level of VEGF in the
microenvironment by using the implantation of
engineered myoblasts converted pathological angiogenesis into therapeutic angiogenesis in mice.71
Combinations of several angiogenic factors induce
a more secured and stable vasculature than the
administration of single growth factors.72 This
concept has been tested recently in a clinical
phase-I trial by introducing the pro-angiogenic
transcription factor hypoxia-inducible factor 1a,
which is expected to activate all genes needed for
proper microvessel growth.73 Infusion of bonemarrow-derived mononuclear cells is a promising
possibility for inducing coordinated microvessel
growth. Endothelial progenitor cells from this
source assist the angiogenic process indirectly by
secreting a variety of factors that induce angiogenesis, vasculogenesis or vasodilation, and stem/
progenitor cell mobilization and recruitment, or
reduce apoptosis.74 Direct endothelial progenitor
cell contributions to neovascularization occur
through differentiation into endothelial cells or
transdifferentiation into vascular smooth-muscle
cells and cardiomyocytes to form the structural
components of capillaries, arterioles and the myocardium.75–77 Clinical investigations of endothelial
progenitor cells for regenerative medicine are now
under way.78
Theoretically, therapeutic angiogenesis might also
be administered as an anti-hypertensive therapy.
In animal models, a direct link between blood
pressure reduction and microvessel formation has
been demonstrated.
An engineered variant (COMP-Ang-1)79,80 of angiopoietin-1, a potent angiogenic growth factor,
was tested to enhance endothelial protection and
microvessel density in SHR.81 COMP-Ang-1 reduced
microvascular rarefaction and tissue damage in the
heart and the kidney and, intriguingly, also prevented the development of hypertension. These
effects on systolic blood pressure disappeared when
SHRs were pretreated with soluble Tie2 receptor,
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R Humar et al
777
suggesting that the therapeutic effects of COMPAng-1 were mediated by the endothelium.81
Hypoxia served as the main trigger for angiogenesis, in a recent study, in SHRs.82 Chronic
normobaric hypoxia (10% O2) decreased vascular
resistance and, subsequently, systolic blood pressure by 26% already after 3 weeks when compared
with normoxia (21% O2).82 Treatment with neutralizing VEGF-A antibody abrogated hypoxia-induced
angiogenesis and subsequently worsened arterial
hypertension. Thus, chronic hypoxia activates
VEGF-A-induced angiogenesis, and thereafter prevents or normalizes microvascular rarefaction and
the occurrence of hypertension.82 These are first
experimental studies in animals to demonstrate that
reversing microvascular rarefaction by angiogenic
triggers could be a new way of treating hypertension
and target organ damage (Figure 1).
A normobaric oxygen content of 10%, which was
used in the study by Vilar et al.82 corresponds to an
altitude of approximately 5000 m, which is close
to the altitude of the highest permanent human
habitation—La Rinconada, a mining village in
southern Peru at almost 5100 m. Indeed, persons
living in Peruvian communities at altitudes over
4000 m very rarely suffer from particularly systolic
hypertension when compared with those living at
sea level, as detected by a study conducted in more
than 7000 persons 40 years ago.83
Established anti-hypertensive therapies
may reverse microvascular rarefaction
Pro-angiogenic therapy that is designed specifically
to reduce blood pressure in hypertensive patients
has not been addressed thus far. Clinical studies in
hypertensive patients have focused mainly on
blood pressure lowering, vasodilation and vasoconstriction, vascular rheology, vascular stiffness
and reversal of target organ damage. However, a
few clinical studies have explored the effects of
anti-hypertensive drugs on the microvasculature.
Indeed, effective and long time anti-hypertensive
Figure 2 (a) Angiotensin-converting enzyme (ACE) inhibition can reverse microvascular rarefaction. ACE inhibition causes bradykinin
(BK) to accumulate that increases pro-angiogenic inducers such as nitric oxide (NO) and vascular endothelial growth factor (VEGF)
mainly by the BK type 2 receptor and its interaction with the VEGF receptor 2.50,88,92 Also angiotensin II can be pro-angiogenic through
the angiotensin type 2 receptor, which increases BK levels.103 Angiotensin type 2 receptor may be specifically activated when angiotensin
II type 1 receptor blockers (ARBs) block binding to the angiotensin type 1 receptor. (b) Vasoactive peptides stabilized by ACE inhibition
induce endothelial sprouts in vitro. BK, BK1n agonists and ACE inhibition by enalapril induce the outgrowth of capillary sprouts from
pieces of mouse hearts cultured in a fibrin gel under hypoxic conditions. The extent and morphology of endothelial sprouts is
comparable to those induced by VEGF.50
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R Humar et al
778
treatment normalized vascular structure and reversed microvascular rarefaction in hypertensives.
Capillary density in non-diabetic hypertensive
patients increased compared with that in untreated patients.84 Furthermore, the ACE-I lisinopril
reduced retinal microvascular rarefaction after 52
weeks of treatment in previously untreated hypertensive patients.35 The regenerative effect of
anti-hypertensive treatment appears to be specific
for the type of drugs used: ACE-I, but not b-blockers,
normalized the structure of small subcutaneous
arteries and arterioles of patients with essential
hypertension after a 12–month treatment.85,86 Thus,
the ability of anti-hypertensive agents to normalize microvascular structure may be restricted to
drugs that present vasodilator activity, such as
ACE-I, excluding drugs that lower blood pressure
through a reduction in cardiac output, such as
b-blockers.84
The pro-angiogenic effects of ACE-Is on the
microvasculature have been extensively studied in
experimental animal and in vitro models: ACE-Is
increased myocardial capillary density in SHRs,12 in
hind limb ischaemia of rabbits,87 of mice88,89 and in
different rat models of obesity (Figure 2a, for
specific review see Battegay et al.90). Inhibition of
the breakdown of bradykinin (BK) and consecutive
angiogenic activity of BK rather than angiotensin-IImediated effects most likely accounts for ACE-Itriggered angiogenesis (Figures 2a and b). Knockout
of the BK B2 receptor blunted ACE-I-induced
vascularization of mouse ischaemic legs88 and
vascularization in an in vitro model of the hypoxic
heart.50 Figure 2b depicts angiogenic activity in vitro
of BK, BK1 agonist and the ACE-I enalalpril from
this study.50 Further studies in rat models suggest
that ACE-I-induced neovascularization depends on
both BK B1 and B2 receptors.12,91,92
The ACE-I captopril represents an exception to
the ‘rule’ that ACE-Is are generally pro-angiogenic:
captopril, with its reactive sulfhydryl group, inihibits metalloproteinases93 and increases the formation of the endogenous and potent angiogenic
inhibitor angiostatin.94 Captopril reduced microvascular growth in hypertensive and normotensive
rats95 and the capillary-fibre ratio in ischaemic hind
limbs of rats.96 ACE-Is, which differ from captopril
chemically, however, do not possess these specific
anti-angiogenic properties.
The anti-hypertensive drug class of angiotensin II
type 1 receptor blockers also present vasodilator
activity and can increase capillary density. The
angiotensin II type 1 receptor blocker losartan,97–99
but not valsartan,100 increased microvessel density
in rat models of hypertension and cardiac failure.
In a study in 70 hypertensive patients, losartan
also reduced vascular rarefaction and hypertrophy
and improved insulin sensitivity after 3 years of
treatment, compared with the b-blocker atenolol.101
In line, in SHR, the angiotensin II type 1 receptor
blocker olmesartan improved insulin signalling and
Journal of Human Hypertension
prevented microvascular rarefaction in the skeletal
muscle;102 thus, theoretically, restored insulin signalling may also contribute to vascular proliferation
and angiogenesis.
Taken together, these data suggest that the angiotensin II type 1 receptor blockers losartan and
olmesartan, but not valsartan exert angiogenic
effects and improve microvessel integrity.
Conclusion
The review of results from experiments in animal
models of hypertension, leads us to conclude that
microvascular normalization and the abrogation of
microvascular rarefaction can likely improve hypertension and hypertension-induced target organ
damage. Furthermore, numerous, large clinical
studies of human cancer patients who are being
treated with anti-angiogenics also suggest a reciprocal proportionality between the number of functional microvessels and hypertension. However,
pro-angiogenic therapy for the treatment of ischaemic peripheral and cardiac diseases is still in its
infancy and is far from being used as new therapy to
treat essential hypertension. The mechanisms and
means of inducing microvessels safely are currently
being explored, developed and assessed in clinical
trials. It remains to be shown if blood pressure
changes in the outcomes of these trials will match
alterations in microvascular densities.
At present, the only available method for
normalizing or increasing the microvasculature in
hypertensive patients is through long-term antihypertensive treatment. Drugs, that have a potent
anti-remodelling effect or the potential to induce
microvessels, particularly the non-captopril class
ACE-I such as lisinopril or enalapril and potentially
angiotensin II type 1 receptor blockers like losartan,
might be desirable to treat hypertension, specifically
when structural rarefaction precedes the onset of
hypertension.
It is important to understand better the mechanisms of microvascular rarefaction. Further studies
on the genetics of impaired angiogenesis during
development should add to our understanding of
the predisposition to hypertension. A continued
characterization of angiogenic responses and
changes of microvessel network patterns in different
tissues and those that occur over the time course of
treated or untreated hypertensive disease are necessary. Here, new non-invasive diagnostic tools such
as the analysis of retinal microvessels may offer new
prospects.
Conflict of interest
The authors declare no conflict of interest.
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779
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