Experimental Models for Vascular Endothelial Dysfunction
Dhvanit Indravadan Shah
Trends in Medical Research,
2007, 2(1), 12-20.
The endothelium is recognized as a physical barrier between blood and vascular wall. It regulates vascular tone, endothelial permeability and vascular growth. Dysfunction of endothelium has been characterized by partial or complete loss of balance between vasorelaxation and vasoconstriction, thrombosis and thrombolysis. Various experimental evidences have shown that endothelial dysfunction mainly occurs due to reduced nitric oxide production and increased oxidative stress. Vascular endothelial dysfunction is associated with pathogenesis of atherosclerosis, hypertension, diabetes mellitus, coronary artery diseases and stroke. In the present review, we have discussed various recently developed animal models for vascular endothelial dysfunction, which may open new vista to develop agents for improving vascular endothelial function.
||Pharmacological mechanisms involving in the pathogenesis of
vascular endothelial dysfunction. HFD indicates high fat diet, STZ indicates
streptozotocin, DOCA indicates deoxycortisone acetate, TAB indicates transverse
aortic banding, LPS indicates lipopolysaccharide, eNOS indicates endothelial
nitric oxide synthase and ROS indicates reactive oxygen species
Experimental Models to Induce Vascular Endothelial Dysfunction
The animal models for vascular endothelial dysfunction share many features
which are universal to human endothelial dysfunction and have been depicted
by targeting eNOS, xanthine oxidase and NADH/NADPH oxidase pathways (Fig.
Hypertension-induced Vascular Endothelial Dysfunction
Endothelium plays an important role in regulation of blood pressure (Taddei
et al., 2001). Hypertension has been shown to cause vascular endothelial
dysfunction (Sainani and Maru, 2004). The method commonly used to induce hypertension
in rats is goldblatt techniques such as 2-kidney 1-clip model and 1-kidney 1-clip
model, which have been demonstrated to increase arterial blood pressure, total
peripheral resistance (TPR) and decrease endothelium dependent relaxation to
acetylcholine (Ach) (Share et al., 1982; Sventek et al., 1996).
Recently we have shown that uninephrectomy followed by administration of DOCA
salt (40 mg kg-1, s.c.) in olive oil along with 1% NaCl and 0.5%
KCl twice weekly for 6 weeks has produced vascular endothelial dysfunction (Shah
and Singh, 2006a). Further, treatment with L-NAME (eNOS inhibitor) (50 mg kg-1
day-1) for 6 weeks has been shown to increase blood pressure and
reduce endothelium dependent relaxation in rats (Kung et al., 1995).
Infusion of angiotensin-II (0.7 mg kg-1 day-1) for 5 days
has been noted to increase systolic blood pressure, generation of superoxide
anion and cause impairment of Ach-induced relaxation (Rajagopalan et al.,
1996). Moreover, chronic administration of ethinyl estradiol (1.5 mg kg-1
day-1) for 3 weeks has been shown to increase blood pressure and
consequently reduce endothelium dependent relaxation (Thakre et al.,
2000). Furthermore moderately high fat diet administration for 10 weeks has
been shown to develop vascular endothelial dysfunction in rats characterized
by hypertension, increase in reactive oxygen species (ROS) and lipid peroxidation
(Dobrian et al., 2001). Rats treated with single injection of monocrotaline
(40 mg kg-1 or 100 mg kg-1) has increased mean pulmonary
arterial pressure, ventricular hypertrophy and produced injury to endothelium
of pulmonary artery (Gout et al., 1999; Leung et al., 2003). Spontaneously
Hypertensive Rats (SHR) show cardiovascular responsiveness such as increase
in blood pressure, total peripheral resistance and intravascular volume due
to fluid retention and have been demonstrated to decrease endothelium dependent
relaxation (Sunano et al., 1989).
Diabetes-induced Vascular Endothelial Dysfunction
Diabetes is characterized by hyperglycemia which is an independent risk
factor for the development of cardiovascular diseases (Nakagami et al.,
2005). Endothelial dysfunction plays an important role in pathogenesis of diabetic
vascular diseases. Several mechanisms have been reported in diabetes-induced
impairment of endothelium dependent relaxation including impaired signal transduction
availability and impaired release of EDRF (De Vriese et al., 2000). Recently,
from our laboratory, it has been shown that administration of streptozotocin
(55 mg kg-1, i.p. once) in rats produced diabetes and consequently
induced vascular endothelial dysfunction (Shah and Singh, 2006b-d).
Hyperhomocysteinemia-induced Vascular Endothelial Dysfunction
One of the most consistent finding observed in the studies of experimental
hyperhomocysteinemia is impairment of NO mediated vasodilation (Lentz et
al., 2003). Hyperhomocysteinemia-induced increase in reactive oxygen species
may lead to oxidative inactivation of endothelium derived NO (Eberhardt et
al., 2000). Further, hyperhomocysteinemia has been shown to elevate asymmetric
dimethyl arginine (ADMA) which is an endogenous eNOS inhibitor (Cooke, 2000).
Recently, we have shown that hyperhomocysteinemia-induced endothelial dysfunction
in rats can be produced by administration of L-methionine (1.7%W/W, p.o., daily)
suspension in 0.1% CMC for four weeks (Shah and Singh, 2006b-d).
High Fat Diet-induced Vascular Endothelial Dysfunction
Recently, our laboratory has shown that high fat diet in composition of
5% w/w cholesterol, 10% w/w lard fat, 0.1% w/w sodium cholate and 1% w/w coconut
oil mixed with standard chow diet has produced vascular endothelial dysfunction
(Shah and Singh, 2006a). Combination of methionine (1%) and cholesterol (0.5%)
diet has been noted to abolish endothelium dependent relaxation in rabbits (Zulli
et al., 2003). High fat diet comprising of pig chow supplemented with
2% cholesterol, 17.1% coconut oil, 20.3% corn oil and 0.7% sodium cholate has
been reported to decrease endothelium dependent relaxation and eNOS level in
pigs (Henderson et al., 2004).
Hyperuricemia-induced Vascular Endothelial Dysfunction
It has been suggested that uric acid may induce vascular endothelial dysfunction
by inhibiting endothelial NO production and increasing ROS level (Kanellis and
Kang, 2005). Mild hyperuricemia can be induced by administrating oxonic acid
(750 mg kg-1 day-1, p.o.) in rats (Khosla et al.,
2005). Further, hyperuricemia is induced by administration of yeast extract
paste (20-30 mg kg-1 day-1) for 7 days in rats and mice.
Yeast would disturb normal purine metabolism by increasing xanthine oxidase
activity and generating large quantities of uric acid with ROS and this model
has been shown to be similar to human hyperuricemia (Chen et al., 2006).
Heart Failure-induced Vascular Endothelial Dysfunction
Endothelial dysfunction is a newly discovered hallmark of heart failure
which is characterized by decreased release of EDRF in vasculature and increased
generation of oxygen free radicals. Vascular endothelial dysfunction is induced
by left coronary artery ligation model of heart failure in rats (Indik et
al., 2001). Partial aortic constriction has been shown to produce pressure
overload and consequently ventricular hypertrophy (Balakumar and Singh, 2005,
2006a, b, c). Pressure overloaded ventricular hypertrophy was induced in guinea
pig by placing a hemoclip of 0.5 mm in diameter around a sub diaphragmatic aorta
just above the renal arteries (Lang et al., 2000; Bell et al.,
2001) which has been shown to increase oxidative stress and consequently produce
vascular endothelial dysfunction. Further transverse aortic banding (TAB) for
2 to 11 weeks is employed to produce vascular endothelial dysfunction in mice
(Ogita et al., 2004).
Oestrogen Deficiency-induced Vascular Endothelial Dysfunction
Oestrogen regulates the endothelial nitric oxide synthase activity either
genomically by modulating its expression (Levin, 2005) or nongenomically by
regulating its activity (Chambliss et al., 2002). The incidence of cardiovascular
disorders such as hypertension, atherosclerosis and coronary artery disease
are noted to increase in oestrogen deficiency associated with menopause. The
endothelial dysfunction as a result of menopause is characterized by increase
in plaque formation and intimal thickening (Squadrito et al., 2000; Beral
et al., 2002). Surgical oestrogen deficiency by ovariectomy impairs Ach-induced
endothelium dependent relaxation (Walker et al., 2001). To induce endothelial
dysfunction by ovariectomy, rats were anaesthetized with chloral hydrate (250
mg kg-1 i.p.) and incision was made in right and left dorsal
side of flanks. Ovaries along with uterus were pulled out and suture was applied
at the end of uterus and beginning of ovary. The ovaries on both sides were
removed. The uteri on both sides were pushed back and incisions were sutured
in layers. Neosporin antibiotic powder was applied on wounds and animals were
allowed for 4 weeks to produce vascular endothelial dysfunction.
Nicotine-induced Vascular Endothelial Dysfunction
Cigarette smoking is a strong risk factor for vascular diseases and known
to cause dysfunction of endothelium (Zhang et al., 2006). Nicotine contributes
to smoking-induced endothelial dysfunction because of its ability to impair
endothelium dependent vasorelaxation. Administration of nicotine (2 mg kg-1
day-1 i.p.) for 4 weeks has been shown to decrease bradykinin mediated
endothelium dependent vasodilation in rats (Paganelli et al., 2001; Luo
et al., 2006).
Endotoxic Shock-induced Vascular Endothelial Dysfunction
Endothelial dysfunction plays a crucial role in pathophysiology of septic
shock due to gram-negative bacteria (Cotran and Pober, 1990). Endothelium derived
NO production has been noted to be reduced during endotoxemia (Young et al.,
1991; Myers et al., 1995). A single injection of endotoxin (E. coli)
(15 mg kg-1 i.v.) has been shown to produce vascular endothelial
dysfunction in rats within 6 h. Further, in a rabbit model of endotoxic shock,
a single lipopolysaccharide (LPS) bolus (0.5 mg kg-1 i.v.). Escherichia
coli endotoxin) has produced vascular endothelial dysfunction in about 5
days (Wiel et al., 2000).
Arsenic-induced Vascular Endothelial Dysfunction
Arsenic, a ubiquitous element distributed in the environment and contaminated
drinking water is the main source of arsenic (Abernathy et al., 1999).
Arsenic has been suggested to inhibit eNOS and produce excessive ROS which contributes
to endothelial dysfunction. Chronic arsenic exposure has been associated with
diabetes, cardiovascular diseases (Rossman, 2003; Tseng, 2004) and cerebrovascular
disorders (Wang et al., 2002; Simeonova et al., 2003). Continuous
administration of arsenate (5 mg L-1) in drinking water for 18 weeks
has been shown to produce vascular endothelial dysfunction in rabits (Kumagi
and Pi, 2004).
Glutathione Peroxidase Deficiency-induced Vascular Endothelial Dysfunction
Glutathione peroxidase (GPx1) is an antioxidant enzyme plays an important
role in protection of cells against oxidative stress (Raes et al., 1987).
GPx-1 deficiency directly induces an increase in vascular oxidative stress and
decrease in eNOS mediated NO bioavailability (Schachinger et al., 2000;
ODonnell and Freeman, 2001). Glutathione peroxidase deficiency-induced
vascular endothelial dysfunction is shown in murine model of homozygous deficiency
of GPx-1 (GPx-1-1). Mesentric artery of GPx-1-1 mice demonstrated
paradoxical vasoconstriction to β-methacholine and bradykinin where as
wild type (WT) mice showed dose-dependent vasodilation in response to both agonists
(Forgione et al., 2002).
Hypochlorite-induced Vascular Endothelial Dysfunction
It has been suggested that blood vessels exposed to hypochlorite (HoCl)
exhibit a defect in endothelium derived NO bioavailability manifested as impaired
endothelium dependent arterial relaxation (Stocker et al., 2004). HoCl-induced
vascular endothelial dysfunction may be due to reduction in NO production by
decreasing eNOS level and increasing ROS production (Nuszkouski et al.,
2001; Stocker et al., 2004). Pretreatment with HoCl (400 μM) for
2 h has been shown to produce impaired Ach-induced relaxation in rabit aortic
ring preparation (Witting et al., 2005).
Excessive Glucocorticoid-induced Vascular Endothelial Dysfunction
Glucocorticoids (GC) have been used widely for the treatment of patients
with various disorders including autoimmune disorders. GC such as prednisolone,
methylprednisolone and dexamethasone are often limited by several adverse reactions
associated with vascular system such as coronary artery diseases, hypertension
and atherosclerosis (Ross and Linch, 1982; Saruta, 1996). Various clinical findings
suggest that excessive GC causes overproduction of ROS and reduction of NO availability
leading to vascular endothelial dysfunction in human subjects (Iuchi et al.,
2003). However this has not been well demonstrated in suitable animal models.
Hypertension, diabetes, hyperhomocysteinemia and hypercholesterolemia-induced vascular endothelial dysfunction are the commonly used experimental models since these models are reflecting clinical similitude of vascular endothelial dysfunction. Developing new models employing recent advances in pathophysiology of vascular endothelial dysfunction can accelerate research in developing novel therapeutic agents to improve vascular endothelial function." class="btn btn-success" target="_blank">View Fulltext
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