Mechanisms of endothelial dysfunction in obesity-associated hypertension

Abstract

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.

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Volume 45 (5) 376-472 May 2012
Braz J Med Biol Res, May 2012, Volume 45(5) 392-400
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Mechanisms of endothelial dysfunction in obesity-associated
hypertension
N.S. Lobato, F.P. Filgueira, E.H. Akamine, R.C. Tostes, M.H.C. Carvalho and Z.B. Fortes
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Brazilian Journal of Medical and Biological Research (2012) 45: 392-400
ISSN 0100-879X Review
Mechanisms of endothelial dysfunction
in obesity-associated hypertension
N.S. Lobato1,3, F.P. Filgueira1, E.H. Akamine1, R.C. Tostes2,
M.H.C. Carvalho1 and Z.B. Fortes1
1Departamento de Farmacologia, Instituto de Ciências Biomédicas,
Universidade de São Paulo, São Paulo, SP, Brasil
2Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo, Ribeirão Preto, SP, Brasil
3Departamento de Ciências Biológicas, Universidade Federal de Goiás, Jataí, GO, Brasil
Abstract
Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically
increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or
maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk
factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed
to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction
and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system
and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular
function and a better understanding of how vascular function can be inuenced by these systems would facilitate the develop-
ment of new therapies for treatment of obesity-associated hypertension.
Key words: Hypertension; Obesity; Endothelial dysfunction; Oxidative stress; Renin-angiotensin system; Nitric oxide
Introduction
www.bjournal.com.brBraz J Med Biol Res 45(5) 2012
Correspondence: Z.B. Fortes, Departamento de Farmacologia, Instituto de Ciências Biomédicas, USP, 05508-900 São Paulo, SP,
Brasil. Fax: +55-11-3091-7317. E-mail: zbfortes@icb.usp.br
Received July 13, 2011. Accepted April 2, 2012. Available online April 13, 2012. Published May 7, 2012.
Obesity is a major worldwide public health problem
(1,2), especially in the United States, where approximately
300,000 deaths each year have been attributed to over-
weight or obesity. The worldwide prevalence of obesity has
rapidly risen to epidemic proportions in the past decades, not
only in industrialized nations but also in developing countries
(1,2). Current estimates indicate that more than 1 billion
people in the world are overweight or obese, compared to
850 million who are underweight (3). In the United States,
obesity continues to be a leading public health concern. At
least 65% of adults are overweight, and approximately one-
third of adults are obese with a body mass index (dened
as kg weight/m2 height) of more than 30 (1). An alarming
increase in the prevalence of obesity has also been observed
in Brazil. When data from the 1970s showed undernutri-
tion as the main nutritional problem in Brazil, obesity was
still considered a minor issue. With time, this scenario has
changed dramatically, with a strong reduction of undernu-
trition and the prevalence of obesity constantly growing in
the Brazilian population: from 5.7% in 1974/1975 to 9.6%
in 1989, to 11.4% in 2006, and then to 13.9% in 2009
(4,5). Changes in the quality, quantity and source of food
consumed, combined with a decrease in levels of physical
activity among the genetically predisposed population, have
led to the increased prevalence of obesity (3).
Associated with obesity is hypertension, considered as
the primary mediator of the development of obesity-induced
cardiovascular diseases (6). Clinical and experimental
studies have consistently indicated that excess weight
predicts the development of hypertension (7,8). Although
the importance of obesity as a cause of hypertension is well
established, the excess weight-induced physiological and
molecular mechanisms that mediate high blood pressure
are only beginning to be elucidated. Several mechanisms
with therapeutic implications as potential causes of obesity-
induced hypertension have been identied in the last few
years. Of great interest are observations on endothelial
dysfunction in obesity, which could contribute to hyperten-

Endothelial dysfunction in obesity-associated hypertension 393
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sion. It is well established that obesity impairs the vasodi-
lating properties of the endothelium leading to endothelial
dysfunction (9), which in turn can be considered to be the
rst step in the progression of cardiovascular disease (6).
Additional mechanisms, still related to endothelial dys-
function, have been proposed to mediate hypertension in
obese patients. These include: increase in both peripheral
vasoconstriction and renal tubular sodium reabsorption,
increased sympathetic activity, overactivation of the renin-
angiotensin system (RAS), and insulin resistance (Figure
1). The intra-abdominal visceral deposition of adipose tissue
is also considered to be a contributor to the development of
hypertension in obese individuals (7,8). In addition to these
advances, a revolution in our understanding of mechanisms
regulating appetite, metabolism, and adiposity has occurred
since the discovery of the endocannabinoid system more
than 10 years ago (10,11). This system is activated in obese
individuals and might mediate the effects of obesity on the
development of the metabolic and vascular alterations of
hypertension.
If these advances can translate into safe and effective
pharmacological treatment of obesity, this would also greatly
impact the management of obesity-associated hyperten-
sion. Considering this, in the present section, an overview
of the advances in the understanding of the pathophysiology
of obesity-associated hypertension, focusing on the role of
endothelial dysfunction, will be addressed. We also outline
the function of the main modulating systems of the develop-
ment of hypertension and obesity. A better understanding
of how the vascular function can be inuenced by these
systems would facilitate therapeutic approaches to the
treatment of obesity-associated hypertension.
Endothelial dysfunction: linking obesity
and hypertension
The vascular endothelium plays an important role in
the control of vascular homeostasis. Besides providing a
physical barrier between the lumen and the vessel wall,
the endothelium actively regulates the basal vascular tone
and reactivity in physiological conditions (12). Endothelial
dysfunction, represented by an altered ability of the endothe-
lium to maintain vascular homeostasis through the release
of endothelium-derived relaxing factors and endothelium-
derived contracting factors, is present in human obesity
and associated comorbidities (12), promoting changes in
pressure and ow patterns and, consequently, resulting in
obesity-associated hypertension. Even in normotensive
subjects, endothelial function progressively deteriorates
as blood pressure rises (13).
Endothelial dysfunc-
tion is an important risk
factor for hypertension
because it leads not
only to functional altera-
tions, represented by the
impaired control of the
vascular tonus, but also
to structural changes,
such as thickening of
the intima and media
of the vessel wall. The
association between en-
dothelial dysfunction and
increased blood pres-
sure in obesity comes
from studies showing
that obese individuals
display blunted vasodi-
latation in response to
classical endothelium-
dependent vasodilators
such as acetylcholine in
resistance arteries, as
well as reduced capillary
recruitment in response
to reactive hyperemia
and shear stress (13,14)
and that the severity of
endothelial dysfunction
Figure 1. Mechanisms involved in obesity-associated hypertension. WAT = white adipose tissue; SNS
= sympathetic nervous system; RAS = renin-angiotensin system.

394 N.S. Lobato et al.
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Braz J Med Biol Res 45(5) 2012
correlates with the degree of visceral adiposity (14).
Although the mechanisms linking obesity with endothe-
lial dysfunction have not yet been fully claried, several
factors have been proposed to mediate this process (Figure
2). Results obtained with experimental models of obesity-
associated hypertension indicate a potential role for vascular
proinammatory factors and oxidative stress on endothelial
dysfunction in this condition. Mice with high-fat diet-induced
obesity display increased blood pressure and impairment
in the relaxation of the aorta in response to acetylcholine,
an endothelium-dependent vasodilator. The endothelial
dysfunction in this model has been proposed to be a con-
sequence of the reduced antioxidant defense and the local
activation of the nuclear factor κB (NF-κB) pathway (15). In
a model of hypertension without obesity, high activation of
NF-κB and increased su-
peroxide (O2-) generation
are observed in the vascu-
lar wall (16), indicating that
these two factors may be
the link between obesity
and hypertension.
Decreased nitric oxide
(NO) bioavailability has
been reported to play a
major role in endothe-
lial dysfunction in obesity-
associated hypertension
(17,18). High O2- levels
as a consequence of in-
creased generation of reac-
tive oxygen species (ROS)
or reduced antioxidant
defense contribute to de-
creasing NO bioavailability.
Endothelial nitric oxide syn-
thase (eNOS) uncoupling,
a process in which eNOS
generates O2- instead of
NO when the concentra-
tions of either L-arginine,
the substrate of NOS, or
tetrahydrobiopterin (BH4),
a cofactor of the enzyme,
are depleted, may also
mediate decrease in NO
bioavailability (19). The
crucial role of uncoupled
eNOS as a O2- producing
enzyme has been reported
in hypertension (19) and
diabetes (20). In a model of
obesity without high blood
pressure or hyperglycemia,
the detrimental impact of
obesity on endothelial function in the microvasculature is
also attributable to the reduced NO bioavailability as a con-
sequence of uncoupled eNOS (21). These ndings indicate
the presence of uncoupled eNOS in obesity as a primary
event before the establishment of comorbidities.
Another factor that has been suggested to be associ-
ated with the increased generation of ROS in obesity and
hypertension is the enzyme NAD(P)H oxidase (the main
source of O2- in the vasculature). Excessive O2- generation
from AT1-dependent overexpression of NAD(P)H-oxidase
subunits was demonstrated in spontaneously hypertensive
rats (22). In a similar way, increased O2- derived from
NAD(P)H oxidase was found to impair the endothelial func-
tion of the aorta from Zucker fa/fa rats, a model of obesity
and insulin resistance (23).
Figure 2. Putative mechanisms of endothelial dysfunction in obesity-associated hypertension. De-
creased nitric oxide (NO) bioavailability as a consequence of uncoupled endothelial nitric oxide syn-
thase (eNOS), a process in which eNOS generates superoxide (O2-) instead of NO when the concen-
trations of either L-arginine (L-arg), the substrate of NOS, or tetrahydrobiopterin (BH4), a cofactor of
the enzyme, are depleted, may mediate endothelial dysfunction in obesity-associated hypertension.
Increased reactive oxygen species generation as a consequence of increased NF oxidase and NF-
κB activity and reduced superoxide dismutase (SOD) activity also contribute to decreasing NO bio-
availability in this situation. Increased production of endothelium-derived contractile factors (EDCFs),
including prostanoids (PGF2α and TX2), angiotensin II (Ang II) and endothelin I (ET-1) constitute
additional mechanisms involved in endothelial dysfunction in obesity-associated hypertension. A po-
tential role for perivascular adipose tissue (PVAT) in the vascular dysfunction of obesity has also been
proposed. PVAT can reduce adenosine monophosphate-activated protein kinase (AMPK) activation
and increase the NAD(P)H oxidase-induced O2- production leading to reduced NO production. AA =
arachidonic acid; ACE = angiotensin-converting enzyme; COX = cyclooxygenase; EC = endothelial
cells; ECE = endothelin-converting enzyme; NF-kB = nuclear factor κB; pET-1 = pro-endothelin 1;
PGI2 = prostaglandin I2; VSMC = vascular smooth muscle cells; WAT = white adipose tissue.

Endothelial dysfunction in obesity-associated hypertension 395
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An additional mechanism involved in vascular dysfunc-
tion in obesity is the disturbance in the vascular prole
of prostanoid release. Overproduction of vasoconstrictor
prostanoids has been reported in obesity-associated co-
morbidities such as diabetes (24). In addition, thromboxane
A2 and prostaglandin H2 (TXA2/PGH2) receptor expres-
sion is enhanced in obesity-associated hypertension (25).
A reduced balance of PGI2 and TXA2 release as a result
of the increased TXA2 and decreased PGI2 levels was
recently reported in obese rats (21). This alteration has
been proposed to be associated with increased conversion
of arachidonic acid to prostaglandins by cyclooxygenase-2
(COX2), an isoform of COX described to be induced speci-
cally under inammatory conditions (21).
Increased production or activity of other vasoconstrictor
substances, such as endothelin-1 (ET-1) and angiotensin
II (Ang II), is also implicated in endothelial dysfunction in
obesity and hypertension (26,27). In hypertensive patients,
increased body mass is associated with enhanced ET-1-
induced vasoconstriction (17), suggesting that this abnor-
mality is a potential mechanism for endothelial dysfunction
and may play a role in the pathophysiology of obesity-related
hypertension.
A potential role for perivascular adipose tissue in the
vascular dysfunction occurring in obesity has also been
proposed. Recent studies have demonstrated that the
adipose tissue surrounding blood vessels is a functional
component of the vasculature, modulating vascular reactiv-
ity and proliferation (18,28,29). It has been demonstrated
that, under physiological conditions, the perivascular fat
attenuated the vascular responsiveness to several con-
strictor agonists, including serotonin, phenylephrine,
and ET-1. This effect was attributable to the activation of
voltage-dependent, delayed-rectier K+ (Kv) channels that
hyperpolarize the vascular smooth muscle cell membrane
(18). Furthermore, it has been shown that perivascular
adipose tissue releases relaxation factors in different vas-
cular beds (18,30). Although these ndings do not provide
an explanation for the association between obesity and
hypertension, recent studies have shown that the ability
of the perivascular adipose tissue to release relaxation
factors is impaired in experimental models of obesity (31).
Additionally, it has been shown that perivascular adipose
tissue impacts vascular function and remodeling through
impairment of both eNOS-mediated vasodilatation and
the AMP-activated protein kinase/mammalian target of
rapamycin (AMPK/mTOR) pathway in rats with high-fat
diet-induced obesity (32). Perivascular adipose tissue has
also been shown to enhance the contractile response of
superior mesenteric arteries from Wistar-Kyoto rats through
the production of superoxide mediated by NAD(P)H oxidase,
and this enhancement involves activation of tyrosine kinase
and the MAPK/ERK pathway (33). On this basis, perturba-
tions in perivascular adipose tissue regulation of vascular
reactivity may contribute to blood pressure elevation in
obesity-related hypertension.
Based on the observations discussed above, it is clear
that the endothelium is a major regulator of vascular reac-
tivity, maintaining the balance between vasodilatation and
vasoconstriction. Disturbance in this balance leading to
endothelial dysfunction is considered an early marker for the
development of cardiovascular diseases. Not surprisingly,
this integral role of the endothelium in vascular health and
endothelial dysfunction in obesity has generated consid-
erable interest in its potential role for the development of
obesity-associated hypertension. Of relevance, although the
effects of perivascular adipose tissue on the vasculature
in the presence of obesity still constitutes a major chal-
lenge, it is well known that this tissue is implicated in the
regulation of vascular function in the physiological state.
Thus, the perivascular adipose tissue also provides an
opportunity to understand how changes in the regulation
of vascular function can contribute to the development of
hypertension in obesity.
Role of insulin resistance in endothelial
dysfunction in obesity-associated
hypertension
Obesity is frequently associated with insulin resistance
and compensatory hyperinsulinemia. Clinical and experi-
mental studies suggest a potential cause-effect relationship
between obesity and insulin resistance, since weight gain
or weight loss is closely correlated with reduction/increase
in insulin sensitivity, respectively (34,35). Insulin resistance
in obesity contributes to a range of metabolic and cardio-
vascular alterations, which would favor the development
of hypertension (36).
Insulin is essential for normal tissue development, main-
taining glucose homeostasis and regulating carbohydrate,
lipid, and protein metabolism (37). This hormone also has
important vascular actions, which include the stimulation of
endothelium-dependent NO release, leading to vasodilata-
tion and increased blood ow, favoring glucose uptake by
skeletal muscle. Another distinct insulin-signaling pathway
in the endothelium is the regulation of the release of the
vasoconstrictor peptide ET-1 (38). The vascular actions of
insulin play a central role in the control of metabolic and
hemodynamic homeostasis under healthy conditions.
The role of insulin resistance in the physiopathology
of hypertension was conrmed by studies showing that
non-obese insulin-resistant patients display the same
prevalence of hypertension when compared to obese
individuals (36,39).
The inuence of insulin on endothelial function has been
extensively studied. It was demonstrated that the effect of
vasodilating agents on endothelial cells depends on a direct
facilitator action of insulin and that in insulin-decient states,
early alterations of the effects of insulin on endothelial cells
might contribute to the impaired reactivity of the microves-

396 N.S. Lobato et al.
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Braz J Med Biol Res 45(5) 2012
sels (40). Consistent with these results are the observations
that treatment with either insulin (20) or the insulin sensitizer
metformin (41) corrects the reduced endothelium-depen-
dent vasodilatation without fully improving the metabolic
parameters of experimental models of diabetes. Impaired
arteriole and venule responses to endothelium-dependent
vasodilators in type 2 diabetes are also corrected by both
acute and chronic insulin treatment (42).
Decreased sensitivity of resistance vessels to endothe-
lium-dependent vasodilatation induced by insulin has also
been observed in obese individuals (43). Clinical studies
have demonstrated a 40 to 50% reduction in endothelium-
dependent vasodilatation induced by insulin in non-diabetic
and diabetic obese patients. This alteration was attributed
to the impaired ability of insulin to stimulate NO produc-
tion by endothelial cells (44). These observations indicate
that obesity and insulin resistance, independently of other
risk factors, are associated with impairment of endothelial
function.
Among the mechanisms proposed to mediate the role of
insulin in the association between obesity and hypertension
is insulin resistance in vascular smooth muscle cells, with
impairment of insulin-mediated ion exchange processes
(Ca2+-ATPase and Na+, K+-ATPase), leading to Ca2+ and
Na+ accumulation on the vascular wall (45,46). This altera-
tion facilitates the action of vasoconstrictor agents such as
Ang II and norepinephrine (47). Insulin resistance in ex-
perimental models of hypertension is also accompanied by
endothelial dysfunction in resistance vessels with impaired
PI3-kinase-dependent NO production and enhanced ET-1
secretion, which may combine with elevated peripheral
vascular resistance and contribute to hypertension in this
model (38). Taken together, these ndings support a role
for several related mechanisms by which insulin resistance
might contribute to the development of endothelial dysfunc-
tion in obesity-associated hypertension.
Sympathetic nervous system and endothelial
dysfunction in obesity-associated
hypertension
The overactivity of the sympathetic nervous system is a
common feature of obesity, and is closely associated with
the cardiovascular and renal alterations observed in this
condition (48). A number of factors may account for this,
including baroreex dysfunction, hypothalamus-pituitary
axis dysfunction, insulin resistance, hyperinsulinemia,
hyperleptinemia, and overactivity of the RAS. Weight loss
reduces blood pressure and the activity of the sympathetic
nervous system (49), conrming that long-term sympatho-
activation is the link between obesity and the increase in
blood pressure (Figure 1).
Leptin has emerged as a link between excess adiposity
and increased cardiovascular sympathetic activity. Besides
having an effect on appetite and metabolism, leptin acts
on the hypothalamus to increase blood pressure through
activation of the sympathetic nervous system (50). Obe-
sity is usually associated with selective leptin resistance,
a condition characterized by resistance to the feeding
and weight reducing effects of leptin, but preservation
of the renal sympathoactivation by this hormone (51).
Hyperinsulinemia may also play a role in the overactivity
of the sympathetic nervous system in obesity. Insulin, like
leptin, causes sympathetic activation in different tissues,
including the kidney (52). The ability of insulin to stimulate
renal sympathetic outow is preserved in experimental
models of obesity, despite the insulin resistance observed
in this condition (53). The elevated circulating levels of
non-esteried fatty acid (NEFA) from visceral fat depots
in obese subjects appear also to mediate the increased
sympathetic activity and, ultimately, the raise in blood pres-
sure (54). Longitudinal and cross-sectional studies also
indicate a role for some newly discovered peptides such
as ghrelin (55) and adiponectin (56), as independent risk
factors for hypertension in obese patients via modulation
of the sympathetic nervous system.
Interactions between autonomic nervous system regula-
tion and endothelial function may provide a mechanism to
explain the endothelial dysfunction occurring in obesity and
hypertension (Figure 1). The sympathetic nervous system
may directly inuence the endothelium. Endothelial cells
possess both α2-adrenoceptors and β-adrenoceptors (57).
Given that activation of endothelial adrenergic receptors
releases endothelium-derived relaxant factors like NO
and endothelium-derived contracting factors such as ET-1
(57,58), disturbances in the balanced release of these fac-
tors as a consequence of altered activity of the sympathetic
nervous system may explain the role of this system in
abnormalities of endothelial function in obesity-associated
hypertension (44). The best evidence of this comes from
studies showing that exaggerated sympathetic nervous
system activation may impair endothelial function and
enhance an endothelium-mediated atherogenic process
(59). Increased levels of catecholamines are also postulated
to induce macrophages into the vessel (60) and increase
uptake of low-density lipoproteins by endothelial cells (61).
Despite this evidence, it is unclear whether the sympathetic
nervous system and endothelial systems are negatively af-
fecting one another, or whether both systems are affected
as a consequence of obesity and hypertension.
Endothelial dysfunction and the RAS
The RAS is another important system involved in hy-
pertension in obesity (Figure 1). Increased activity of the
RAS, represented by increased circulating angiotensinogen,
renin, aldosterone, and angiotensin-converting enzyme
(ACE) activity has been demonstrated in obesity, both
systemically and within adipose tissue, and was directly
related to the mass of adipose tissue (62,63). The signicant

Endothelial dysfunction in obesity-associated hypertension 397
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role for Ang II in stimulating sodium reabsorption, impair-
ing renal-pressure natriuresis and causing hypertension
in obesity is supported by studies showing that a modest
reduction in body weight can lead to a meaningfully re-
duced RAS activity in plasma and adipose tissue, which
parallels a reduction in blood pressure (64,65). A dietary
intervention study in menopausal women showed that a
5% weight loss resulted in a 7-mmHg reduction of blood
pressure. This decrease was accompanied by signicant
declines of serum angiotensinogen (27%), renin (43%) and
ACE activity (12%), as well as angiotensinogen expression
in adipose tissue (20%) (64).
Under physiological conditions, infusion of Ang II causes
redirection of blood ow between different vascular beds
and within the vascular bed of skeletal muscle. This effect
leads to an increase in total muscle blood ow and capillary
recruitment with a consequent increase in insulin-induced
glucose uptake (66). However, in obesity, the RAS seems
to have a detrimental effect on insulin-induced glucose
uptake (65). Additionally, Ang II has been reported to impair
insulin stimulation of insulin receptor substrate 1 (IRS-1)
tyrosine phosphorylation and coupling of the insulin receptor
pathway to PI3-kinase in the vasculature, suggesting that
activation of the RAS may contribute to insulin resistance
in the vasculature (67).
The activation of the RAS may also mediate endothelial
dysfunction in obese individuals. Ang II activates recep-
tors located on either endothelial or smooth muscle cells.
The activation of endothelial receptors is linked to the
production of the contractile peptide ET-1 and ROS. The
effects of Ang II on smooth muscle cells involve contrac-
tion and proliferation (68). The role of the RAS as an
independent factor involved in endothelial dysfunction
in hypertension was conrmed by the observation that
treatment of DOCA-salt hypertensive rats with an ACE
inhibitor corrected the decreased endothelium-dependent
relaxation in response to acetylcholine in aortic rings,
independently of normalizing blood pressure levels (69).
In addition, it was demonstrated that the free fatty acids
(FFA)-induced impairment of endothelial function in obese
individuals was completely prevented by either the AT1
receptor blocker or the ACE inhibitor, which suggests that
an elevation of FFA induces endothelial dysfunction through
activation of the RAS (70). Chronically elevated Ang II can
also increase ROS generation (16,71). ROS generation
can reduce the endothelium-dependent vasodilatation by
impairing NO bioavailability (72). Therefore, these ndings
indicate an important role for the RAS providing another
potential link between obesity and hypertension.
Endocannabinoid system: cardiovascular
effects in obesity and hypertension
The endocannabinoid system has emerged as a highly
relevant topic in the scientic community because of its
important role in the central and peripheral regulation of
food intake and energy balance (73). In fact, it has been
demonstrated that increased activity of the endocannabinoid
system contributes to the increased food intake and the de-
velopment of the cardiovascular risk factors that accompany
weight gain (11). Since increased visceral adiposity can be
considered to be the link between overweight and hyper-
tension, a dysregulated, overstimulated endocannabinoid
system in visceral adipose tissue could indirectly contrib-
ute to visceral obesity-associated hypertension (74,75).
However, endogenous cannabinoid ligands reduce blood
pressure and heart rate and are potent vasodilators in a
number of isolated vascular preparations of normotensive
non-obese animals, which involve endothelium-dependent
and -independent mechanisms (76-79). Thus, the direct
involvement of an overstimulated endocannabinoid system
in the endothelial dysfunction and hypertension occurring in
obesity is not clear. Indeed, the implication of the endocan-
nabinoid system in the vascular dysfunction of hypertension
is controversial. In fact, since increased hypotensive and
vasodilator effects of cannabinoids have been reported in
hypertension (80,81), this system could represent a com-
pensatory mechanism to counteract the increase in arterial
pressure and vascular resistance in hypertension.
The implication of the overstimulated endocannabinoid
system in the endothelial dysfunction and obesity-associ-
ated hypertension has not been claried. A dysfunctional
activity of the endocannabinoid system in obesity could
nullify its compensatory effect to counteract the increase
in arterial pressure and endothelial dysfunction as that ob-
served in hypertension. Therefore, a direct involvement of
the overstimulated endocannabinoid system in endothelial
dysfunction and obesity-associated hypertension cannot
be ruled out and further studies are necessary to clarify
this point.
Conclusion
Reduced NO availability as a consequence of uncou-
pled eNOS and increased NAD(P)H oxidase activity, and
increased production of endothelium-derived contracting
factors (EDCFs) (prostanoids, Ang II, and ET-1) are im-
plicated in endothelial dysfunction in obesity-associated
hypertension. Visceral adiposity and/or perivascular
adipose tissue dysfunction are directly involved in NO/
EDCFs imbalance by promoting a chronic inammatory
state. Moreover, disorders promoted by visceral adiposity
dysfunction can individually impair endothelial function.
Insulin resistance is the most common obesity-promoted
disorder and this condition is characterized by impaired
PI3-kinase-dependent NO production and enhanced ET-1
secretion, which impair the capacity of insulin to promote
a facilitator action of vasodilator agents. Compensatory
hyperinsulinemia due to insulin resistance, hyperleptinemia,
increased activity of the RAS, among other factors, are

398 N.S. Lobato et al.
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Braz J Med Biol Res 45(5) 2012
responsible for the overactivity of the sympathetic nervous
system in obesity-associated hypertension. Disturbances in
the balanced release of NO and constrictor factors stimu-
lated by activation of endothelial adrenergic receptors con-
tribute to the endothelial dysfunction of obesity-associated
hypertension. Besides promoting endothelial dysfunction
through sympathetic overactivation, increased RAS activ-
ity also has a direct impact on endothelial function. Ang II,
by activating receptors located on endothelial or smooth
muscle cells, produces ET-1 and ROS. Finally, increased
activity of the endocannabinoid system contributes to the
pathophysiology of obesity; however, its contribution to the
endothelial dysfunction of obesity-related hypertension has
not been elucidated.
In conclusion, the mechanisms involved in the endothe-
lial dysfunction of obesity-associated hypertension are
various and not mutually exclusive, and in some way they
are redundant (Figure 1). The relative contribution of any
of them is not easily dened. The important advances in
understanding the pathophysiology of obesity-associated
hypertension that have been achieved in the last years
can greatly impact the prevention and the management of
obesity-associated hypertension. Any intervention able to
prevent or reverse obesity-related endothelial dysfunction
might represent a major tool to improve the cardiovascular
outcome of obese patients.
Acknowlegments
The authors are grateful to Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP) for research
support.
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