(Hypertension. 1999;34:89-95.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Attenuated In Vitro Coronary Arteriolar Vasorelaxation to Insulin-like Growth Factor I in Experimental Hypercholesterolemia
From the Division of Internal Medicine and Cardiovascular Diseases (D.H., D.R.H., D.M.R., A.L.) and the Division of Endocrinology and the Endocrine Research Unit (M.F.N., R.A.R.), Mayo Clinic and Foundation, Rochester, Minn; and the Division of Endocrinology and Department of Pediatrics, University of Pennsylvania, Philadelphia (P.C.).
Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu
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Abstract—Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10-12 to 10-7 mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10-4 mol/L NG-monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10-2 mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5±1.0 versus 1.9±0.08 mmol/L; P<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80) or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79±6% versus 42±8%; P=0.01) but not insulin (43±6% versus 53±7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.
Key Words: pigs • arteries • insulin • insulin growth factor • hypercholesterolemia
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Introduction |
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Insulin-like growth factor (IGF) 1 and 2, 7.5-kDa peptides, are the principal ligands of the IGF axis.1 Both are highly homologous in structure and function to proinsulin. Unlike insulin, which is only produced in the pancreas, IGF-1 is produced by various cell types, including endothelial2 and vascular smooth muscle cells.3 IGF-1 is presumed to affect the structural changes associated with atherosclerosis and related conditions.2 3
Both insulin and IGF have diverse vasoactive actions (see Reference 44 ). Although the vasoactive effects of the 2 peptides may be similar, each peptide may have unique effects depending on the vascular bed and the pathophysiological state.5 We have recently demonstrated that both insulin and IGF-1 are coronary epicardial vasorelaxants4 ; these effects were attenuated by inhibitors of the nitric oxide pathway and of potassium channels. Because coronary blood flow is primarily regulated by arterioles and resistance vessels, the in vitro effect of agents on arterioles may be of greater practical significance than epicardial arteries. Hitherto, we are not aware of any study that characterized the effect of insulin and IGF-1 on coronary arterioles.
Experimental hypercholesterolemia in the pig is associated with early coronary atherogenesis6 and altered coronary endothelial function.7 8 9 10 11 The role of the coronary arterioles in the regulation of vascular tone in early coronary atherosclerosis is emerging. Accordingly, we have shown that the altered vasoreactivity associated with hypercholesterolemia may be differentially affected in porcine coronary epicardial arteries and arterioles,7 underscoring the need for the evaluation of both vessel types in pathophysiological states.
The coronary vasoactive effects of insulin-related peptides may be impaired in pathophysiological states associated with altered endothelial function such as diabetes mellitus and hypertension.5 12 13 In particular, a resistance to the renal actions of IGF-1 has recently been reported in spontaneously hypertensive rats, primarily at the arteriolar level.12 13 The present study was therefore designed to examine the hypothesis that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1, primarily at the level of coronary arterioles.
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Animals
The study procedures and handling of animals were reviewed and approved by the Mayo Foundation Institutional Animal Care and Use Committee. Juvenile domestic crossbred pigs were randomly placed on either a normal diet or a diet of 2% cholesterol and 15% lard by weight (TD 93296, Harlan Teklad) for 10 weeks.7 8 9 10 11 At 10 weeks, we determined plasma total cholesterol and low-density lipoprotein levels by applying the technique of Allain et al,14 using a commercial reagent (Roche). The animals were then killed with an intravenous overdose of pentobarbital sodium (30 mg/kg IV, Sleepaway, Fort Dodge Laboratories). After the animals were killed, the hearts were harvested for in vitro analysis.
In Vitro Analysis of Epicardial Arteries
In vitro determination of epicardial reactivity was performed as
we previously described.4 8 Viability of the vessels was
confirmed by a contractile response to 20 mmol/L KCl at baseline
and at 2, 4, and 6 g, each time after the potassium had been
washed out. At 6 g, all vessels were then exposed to substance P
(10-6 mol/L, Sigma), an
endothelium-dependent vasodilator, to verify the
functional integrity of the vascular endothelium. All
chambers were then washed out with the control solution.
After an equilibration period of 30 minutes, epicardial arteries harvested from normal or hypercholesterolemic animals were contracted with endothelin-1 (10-7 mol/L, Phoenix Pharmaceuticals), and after equilibration for 20 minutes, they were relaxed with cumulative concentrations of either 10-12 to 10-7 mol/L regular insulin (Eli Lilly) or 10-12 to 10-7 mol/L IGF-1 (Pharmacia Upjohn). Stock solutions of each agent were freshly prepared for each experiment. Drugs were dissolved in distilled water such that volumes of <0.2 mL were added to the organ chambers. All concentrations are expressed as the concentration within the bath solution. At the end of all experiments, papaverine (10-3.5 mol/L, Sigma) was added to verify that the vessels maintained vasodilating capacity.
A control group was established to verify that the loss of tension was due to insulin and IGF-1 and not due to the loss of the vasoconstrictor effect of endothelin-1: distilled water was added to control vessels (n=5) at the same time insulin and IGF-1 were added in the experimental group. In the control group, no significant vasorelaxation was evident.
To determine the endothelium-dependent vasorelaxation properties of epicardial arteries harvested from normal and hypercholesterolemic pigs, epicardial arteries (n=7 for each group) were first contracted with 10-7 mol/L endothelin-1 and then relaxed with 10-11 to 10-6 mol/L bradykinin (Sigma).
In Vitro Analysis of Coronary Arterioles
In vitro determination of coronary arteriolar reactivity
was performed with the use of a method we previously
described.7 All vessels were first contracted with 60
mmol/L KCl and then relaxed with 10-6 mol/L
bradykinin to determine the integrity of the vessel, as described above
for epicardial vessels. Responses of the pressurized arteries (ie, not
perfused with flow) were measured at a transmural pressure of 50
mm Hg.
To determine the effects of insulin and IGF-1 on coronary arterioles, vessels harvested from normal or hypercholesterolemic animals were first contracted with 10-8 mol/L endothelin-1 and after equilibration relaxed with cumulative concentrations of either 10-12 to 10-7 mol/L insulin or 10-12 to 10-7 mol/L IGF-1. To determine possible mechanisms for the arteriolar vasorelaxation effects of insulin and IGF-1, in particular mechanisms involving the activation of nitric oxide and potassium channels, vessels harvested from additional control animals were exposed to either the nitric oxide synthase inhibitor 10-4 mol/L NG-monomethyl-L-arginine 10-2 mol/L tetraethylammonium (TEA) (Sigma) 20 to 30 minutes before the addition of endothelin-1. The experiments with TEA were also performed in arterioles harvested from hypercholesterolemic pigs and exposed to cumulative concentrations of IGF-1, as were experiments with L-NMMA in arterioles harvested from hypercholesterolemic pigs and exposed to insulin. At the end of all experiments, papaverine (10-4 mol/L) was added to verify that the rings maintained vasodilating capacity.
To determine the endothelium-dependent vasorelaxation properties of arterioles harvested from normal and hypercholesterolemic pigs, arterioles (n=6 for each group) were first contracted with 10-8 mol/L endothelin-1 and then relaxed with 10-11 to 10-6 mol/L bradykinin.
Arteriolar IGF-1 and IGF Binding Protein 2
Immunoreactivity
IGF binding protein (IGFBP) 2 binds IGF and inhibits its
activities.1 15 16 Prior studies have demonstrated that
IGFBP-2 may have a central role in vascular smooth muscle
function.15 16 To assess whether experimental
hypercholesterolemia altered IGF-1 or IGFBP-2
immunoreactivity in porcine coronary arterioles, arterioles
from control (n=5) and hypercholesterolemic animals
(n=5) were dissected and embedded in paraffin. IGF-1 and IGFBP-2
immunohistochemistry studies were performed with an antibody for IGF-1
and IGFBP-2 (UBI), respectively. In brief, slides were deparaffinized,
and nonspecific binding sites were blocked by applying 5% normal goat
serum (Dako) to slides for 10 minutes. The primary antibody for IGF-1
or IGFBP-2 (diluted at 1:10 and 1:200, respectively) in 1% normal goat
serum was applied and incubated overnight at 4°C. The following day
the primary antibody was rinsed off and blotted, and the biotinylated
secondary antisera cocktail goat anti-rabbit (Dako) was diluted at
1:400 and incubated on the slides for 30 minutes. After the slides were
rinsed, streptavidin-horseradish peroxidase (Dako) diluted at 1:500 was
applied. High-powered photomicrographs were obtained from each
specimen.
Two investigators, unaware of the pig's diet, analyzed the intensity and extent of immunoreactivity from 5 random photomicrographs from each animal. The photomicrographs were each graded on a scale from 1 through 4, with 1 being scant, weak staining and 4 extensive, strong staining, as previously described.9 For each animal, an average score was calculated. An average score was then calculated for each group.
Data Analysis
Results are presented as mean±SEM. For epicardial
vessels, the contraction attained with endothelin-1 for each vessel at
baseline was considered baseline (0% relaxation). Subsequent
measurements of coronary artery relaxation are expressed as
percent reduction in contraction (the maximal relaxation attained, with
papaverine being 100% relaxation). In all experiments, n refers to the
number of vessels. For epicardial vessels, experiments were performed
in parallel to preclude a situation whereby all vessels in 1 experiment
were harvested from only 1 animal (on average, each experiment was
conducted with vessels from 3 to 4 animals). For coronary
arterioles, the vessel diameter after contraction with endothelin-1 for
each vessel at baseline was considered baseline (0% relaxation).
Subsequent measurements of coronary artery relaxation are
expressed as percent increase in diameter. For each arteriole, the
maximal relaxation in the passive state (after papaverine) was
considered 100% relaxation.7 For epicardial vessels, each
experiment was performed with arterioles from at least 3 to 4
animals.4 For statistical analysis, ANOVA or
repeated-measures ANOVA followed by Bonferroni's t test was
used. For the immunohistochemistry analyses, an unpaired
t test was used. A 2-tailed P value of 
0.05 was
considered significant.
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Results |
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Lipid Profile
Plasma total cholesterol levels were significantly higher in animals fed a high-cholesterol diet than those in pigs that were given a normal diet (9.5±1.0 versus 1.9±0.08 mmol/L; P<0.0001).
Mean Maximal Luminal Diameter of Arterioles in Each
Protocol
Mean maximal luminal diameters of vessels in the passive state
(ie, after papaverine) in each protocol are depicted in the
Table. Mean maximal diameters ranged from
289±19 to 484±18 µm in the different study protocols, with a
similar mean maximal arteriolar diameter for control and
hypercholesterolemic arterioles. As previously
reported,7 there was no correlation between arteriolar
diameter and the response to vasoactive agents within this range of
diameters (data not shown). The contraction attained with endothelin-1,
expressed as the absolute reduction in diameter in
micrometers, was not statistically different among the
different protocols.
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Mean Maximal Contraction of Epicardial Arteries to Endothelin-1 in
Each Protocol
The mean contraction of epicardial arteries to endothelin-1 in the
different protocols before exposure to insulin or IGF-1 is also
presented in the Table. There was no statistically
significant difference among the 4 groups.
Endothelial Function
Endothelium-dependent epicardial vasorelaxation to
bradykinin was significantly attenuated in
hypercholesterolemic pigs, with both a greater
EC50 and an attenuated maximal response to
bradykinin (Figure 1). Arterioles
harvested from hypercholesterolemic pigs had an
attenuated vasorelaxing response to bradykinin (Figure 2).
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Epicardial Response to Insulin and IGF-1 in Normal and
Hypercholesterolemic Animals
As shown in the left panel of Figure 3, insulin caused a similar
vasorelaxation response in epicardial vessels harvested from normal and
hypercholesterolemic pigs (maximal relaxation of
28±4% and 37±9%, respectively; P=0.80). IGF-1 also
caused epicardial vasorelaxation in normal and
hypercholesterolemic pigs (maximal relaxation of
25±3% and 37±5%, respectively; P=0.12; Figure 3, right). There was no difference in the vasorelaxation response attained
with both agents.
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Arteriolar Response to Insulin and IGF-1 in Normal and
Hypercholesterolemic Animals
In control animals, the vasorelaxation response to IGF-1 was
significantly greater than insulin (maximal relaxation of 79±6% and
43±6%, respectively; P=0.01). As shown in the left panel
of Figure 4, insulin caused a similar
vasorelaxation response in arterioles harvested from normal and
hypercholesterolemic pigs (maximal relaxation of
43±6% and 53±7%, respectively; P=0.99). Moreover, in
hypercholesterolemic arterioles (Figure 4, right), the vasorelaxation response to IGF-1 was significantly
attenuated compared with control (maximal relaxation of 79±6% and
42±8%, respectively; P=0.01).
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Nitric Oxide Pathway and Arteriolar Vasorelaxation to Insulin
and IGF-1
As shown in the top panel of Figure 5, the incubation of control arterioles
with 10-4 mol/L L-NMMA attenuated the
vasorelaxation response to insulin at concentrations
>10-10.5 mol/L (maximal relaxation of 14±6%
and 43±6% with and without L-NMMA, respectively;
P<0.001). A similar response occurred in
hypercholesterolemia (Figure 6; maximal relaxation of 11±8% and
49±7% with and without L-NMMA, respectively; P<0.001).
The response to IGF-1 at concentrations >10-12
mol/L was also attenuated with L-NMMA (maximal relaxation of 15±5%
and 79±6% with and without L-NMMA, respectively; P<0.001;
Figure 5, bottom).
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Potassium Channels and Arteriolar Vasorelaxation to Insulin
and IGF-1
As shown in Figure 5, the incubation of control arterioles
with 10-2 mol/L TEA did not attenuate the
vasorelaxation response to insulin (maximal relaxation of 52±5% and
43±6% with and without TEA, respectively; P=0.93) but
significantly attenuated the response to IGF-1 at concentrations
>10-12 mol/L (maximal relaxation of 58±7% and
79±6% with and without TEA, respectively; P=0.01). The
vasorelaxation of arterioles harvested from
hypercholesterolemic pigs and incubated with TEA before
the exposure to IGF-1 was similar to that of the arterioles that were
not incubated with TEA (P=0.26; Figure 7). Thus, whereas TEA attenuated the
vasorelaxation to IGF-1 in the arterioles of control animals, it did
not in hypercholesterolemic animals.
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IGFBP-2 and IGF-1 Immunoreactivity
IGFBP-2 immunoreactivity was significantly more pronounced among
arterioles from hypercholesterolemic pigs (Figure 8). Immunoreactivity was most prominent
in the medial layer. The mean staining scores for control and
hypercholesterolemic animals were 1.1±0.3 and
3.1±0.4, respectively (P<0.05). IGF-1 was scantly detected
by immunohistochemistry in the endothelial layer and
media of arterioles harvested from hypercholesterolemic
pigs and was more prominent than the control group (3.5±0.3 versus
2.0±0.4; P<0.05; Figure 8).
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Discussion |
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Main Findings
The principal findings of the present study are that both insulin and IGF-1 caused a concentration-dependent vasorelaxing effect of porcine coronary arterioles in vitro, although IGF-1 was more effective. Experimental hypercholesterolemia caused porcine coronary arteriolar endothelial dysfunction in vitro, yet it resulted in an attenuated porcine coronary arteriolar vasorelaxing response only to IGF-1 in conjunction with increased IGF-1 and IGFBP-2 arteriolar expression. Thus, experimental hypercholesterolemia and related pathophysiological states may be associated with a selective resistance to the coronary arteriolar vasorelaxing effects of IGF-1.
Vasorelaxing Effects of Insulin and IGF-1
Studies in animal models and in humans have demonstrated the
vasoactive effects of both insulin and IGF-1 (see Reference 44 ). These
prior studies have also highlighted the diverse vasoactive properties
of the 2 peptides among different species and even among the different
vascular beds of the same organ of a single species. Moreover, although
the 2 peptides often have the same vasoactive effect in a particular
bed, at times these effects may be different and may be differentially
affected by pathophysiological
states.5 The results of the present study extend these
prior studies, demonstrating that both insulin and IGF-1 are
coronary vasorelaxants of porcine coronary arteries and
arterioles in vitro. Furthermore, in contrast to the similar effects
exerted by the 2 peptides on epicardial vessels, IGF-1 was more
effective in causing vasorelaxation of porcine coronary
arterioles.
The peptides belonging to the IGF family interact with specific receptors designated as type 1 and 2 IGF receptors, as well as with the insulin receptor.1 The type 1 IGF receptor binds IGF-1 with high affinity and insulin with low affinity, whereas the insulin receptor binds insulin with high affinity and IGF-1 with lower affinity. The similar concentration-dependent vasorelaxing effect of insulin and IGF-1 on epicardial vessels therefore suggests that each of the 2 peptides exerts its actions through its own receptor and that the postreceptor mechanisms are similar. However, IGF-1 may exert its effects through interactions with the IGFBPs rather than with the IGF receptor.17 18
The greater efficacy of IGF-1 in arterioles compared with insulin even at supraphysiological concentrations of insulin indicates that in porcine coronary arterioles the vasodilator effects of IGF-1 may be mediated through IGF receptors or that IGF receptors are more prevalent at that environment. In addition, the IGFBPs may enhance the IGF effect specifically. For example, IGF-1 may cause the release of IGFBPs with direct effects on the vascular bed through a receptor-independent mechanism.17 18 These IGFBPs, in turn, may inhibit or amplify the effects of IGF-1, thus affecting vasoreactivity. Given that specific inhibitors of the respective receptors are not available, we were unable to determine whether the mechanism is receptor mediated.
Mechanisms for Arteriolar Vasorelaxation
In prior studies, the vasoactive effects of both insulin and
IGF-1 were attenuated or abolished by inhibiting the production
of endogenous nitric oxide with L-NMMA (see Reference 44 ),
yet these effects have been reported by others to be
endothelium independent (see Reference 44 ). In our
previous study, L-NMMA attenuated the epicardial vasorelaxing effects
of both peptides in vessels with and without
endothelium.4 In our present study, we
found that L-NMMA attenuated the vasorelaxing effects of both insulin
and IGF-1 on porcine arterioles. This may indicate that the arteriolar
response to insulin and IGF-1 is dependent, at least partially, on the
nitric oxide pathway. However, L-NMMA potentially has a direct effect
on other pathways such as potassium channels.4 19 This is
supported by the fact that L-NMMA also attenuated the arteriolar
vasorelaxation to insulin in experimental
hypercholesterolemia, a state associated with
reduced nitric oxide activity.9
The vasoactive actions of insulin and IGF-1 may also be related to the activation of potassium channels.4 In our previous study, TEA, the nonselective inhibitor of potassium channels, attenuated the epicardial vasorelaxing effect of both insulin and IGF-1.4 In the present study, TEA attenuated the arteriolar vasorelaxing effect of IGF-1 but not insulin, further supporting the hypothesis that insulin and IGF-1 exert their coronary arteriolar vasoactive effects through different mechanisms.
The response to IGF-1 was attenuated in arterioles harvested from hypercholesterolemic pigs but not in epicardial vessels. In contrast, both epicardial vessels and arterioles from these pigs had an impaired in vitro response to the endothelium-dependent vasodilator bradykinin, indicating epicardial endothelial dysfunction. These findings demonstrate that the vasoactive effects of the IGF peptides may be exerted even in the face of an impaired endothelial nitric oxide pathway.
The exact mechanism for the coronary arteriolar effects of insulin and IGF-1 was not specifically examined in the present study. Our studies with TEA and L-NMMA were designed to demonstrate that the mechanisms for insulin and IGF-1 at the arteriolar level are different. TEA is a nonselective potassium channel inhibitor, affecting both calcium-dependent and voltage-dependent channels.4 As mentioned above, L-NMMA may also exert effects on pathways other than nitric oxide.5 19 Therefore, the precise coronary arteriolar mechanisms for each peptide remain to be elucidated.
Resistance to IGF-1 in Hypercholesterolemia
The selective attenuation of the vasorelaxing effects of IGF-1 on
coronary arterioles in
hypercholesterolemia may involve 1 or more
mechanisms. In our study, TEA attenuated the arteriolar vasorelaxation
response to IGF-1 in control animals but not in
hypercholesterolemic animals, indicating that the
high-cholesterol diet had affected the interaction between
IGF-1 and potassium channels at the arteriolar level. Reduced activity
of potassium channels in experimental
hypercholesterolemia could explain the
attenuated IGF-1 activity. Of interest, Najibi et al20
reported intact potassium channel activity in
hypercholesterolemic rabbits, resulting in a preserved
response to acetylcholine in the presence of reduced nitric oxide
activity. It is therefore more likely that the
hypercholesterolemic state altered the ability of IGF-1
to activate arteriolar potassium channels through a
receptor-related or prereceptor mechanism.
Grant et al21 have reported that concomitant with the increase in local concentrations of IGF-1 and its receptor in atherosclerotic coronary arteries, there is also an increase in the IGFBPs. Of interest, in the present study we also detected higher levels of both IGF and IGFBP-2 in hypercholesterolemic pigs. The IGFBPs modulate the systemic and local actions of IGF-1 through their interaction with the IGF ligand and its availability to the IGF receptor, sometimes enhancing the effects of IGF-1 and sometimes attenuating it.1 This pathway is further modulated by proteases of the IGFBPs. Porcine vascular smooth muscle cells secrete a serine protease for IGFBP-2.15 Experimental hypercholesterolemia in the pig possibly results in a net inhibitory effect on the actions of IGF-1 at the level of the coronary arterioles through local changes in the activity or concentration of the receptors, IGFBPs, or IGFBP proteases. Because we assessed the expression of only 1 IGFBP in the present study (ie, IGFBP-2) and did not evaluate the other members of the axis, a more complex explanation for the arteriolar IGF resistance may emerge.
Conclusion
This study shows for the first time that a
pathophysiological state can be associated with a
selective resistance to the coronary vasoactive effects of
IGF-1, which is independent of resistance to the vasoactive effects of
insulin. Prior studies have implied that changes in the IGF axis may
lead to the structural changes associated with
atherosclerosis and related
diseases.2 3 21 The results of this study complement these
studies, demonstrating that the IGF axis may also be involved in the
functional changes associated with these conditions.
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Acknowledgments |
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This study was supported by the Mayo Foundation, Miami Heart Research Institute, the Bruce and Ruth Rappaport Vascular Biology Program, and the National Institutes of Health (Dr Rizza) (grant DK 29553).
Received January 21, 1999; first decision February 8, 1999; accepted March 15, 1999.
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M. Rodriguez-Porcel, A. Lerman, E. L. Ritman, S. H. Wilson, P. J. M. Best, and L. O. Lerman Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia Circulation, October 24, 2000; 102(17): 2028 - 2030. [Abstract] [Full Text] [PDF]
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