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1 Cardiovascular Research Institute, Department of Medical Physiology, Texas A&M University System Health Science Center, College Station, Texas 77843-1114; and 2 General Pharmacology, Experimental Station, DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Integrin binding by
Arg-Gly-Asp (RGD)-containing peptides has been shown to alter vascular
tone in a variety of blood vessels and has been implicated as a
mechanism of vasoregulation during tissue injury. However, the effect
of these peptides in the coronary circulation has not been examined.
Thus the purpose of our study was to test the hypothesis that integrins
act as receptors linked to the regulation of coronary vasomotor
function. In particular, the ability of RGD-containing peptides to
influence vascular tone by interacting with the
v
3- and
51-integrins was studied in isolated pig
coronary arterioles. All vessels developed basal tone and dilated in a
concentration-dependent manner to soluble peptides cyclic GPenGRGDSPCA
(cyclic RGD), an v3-cyclic-binding peptide (XJ735), DMP7677, an 51-binding
peptide, and to protease-generated (neutrophil elastase) fragments of
denatured collagen type I (a major RGD-containing extracellular matrix
protein). The vasodilations to cyclic RGD, XJ735, and collagen
fragments were almost completely blocked by endothelial removal or by
the cyclooxygenase inhibitor indomethacin. In contrast, after
endothelial removal and incubation with indomethacin, coronary
arterioles showed concentration-dependent constriction to the
51-integrin ligand DMP7677 but not to
cyclic RGD or XJ735. Collectively, our results indicate that activation of endothelial v3- and
51-integrins mediates coronary arteriolar dilation via the endothelial production of cyclooxygenase-derived prostaglandins. These data support a role for integrins in the regulation of coronary vascular tone that may be particularly important
during myocardial injury.
arginine-glycine-aspartic acid; endothelium; v3- and
51-integrins; microcirculation; prostaglandins; vascular tone
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTEGRINS ARE A LARGE
FAMILY of heterodimeric transmembrane glycoproteins that play an
important role in mediating attachment to the extracellular matrix
(ECM) and in serving as receptors for signaling molecules (11,
27). They are composed of one -subunit and one -subunit. A
majority of integrins, including v3 and
51, recognize a conserved amino acid
sequence, Arg-Gly-Asp (RGD) (27). This tripeptide sequence
is found in a variety of ECM molecules, including fibronectin and
collagen (3, 24). Interestingly, in vitro studies have
shown in isolated vessels from a variety of vascular beds that
synthetic RGD peptides (20-22, 28, 31, 34) and
fragments of fibronectin (17) and type I collagen
(22) alter vascular tone. However, there appears to be a
heterogeneous distribution of vascular responses to RGD-containing peptides. For example, Mogford et al. recently demonstrated that interaction of synthetic RGD peptides with the smooth muscle
v3- (22) and endothelial
51-integrins (21) mediates
vasodilation and vasoconstriction, respectively, in the rat skeletal
muscle microvessels. In contrast, Yip and Marsh (34)
showed that an RGD peptide produced smooth muscle-mediated constriction
of isolated rat kidney afferent arterioles. Furthermore, some studies
report an endothelium-dependent vasodilation to RGD peptides (17,
20, 31), whereas others show that smooth muscle-mediated
vasodilation predominates (22, 28). Regardless of the
disparate results, these findings suggest that it is plausible to
postulate a role for integrins in contributing to the local control of
blood flow and regulation of coronary vascular tone.
It is likely that an in vivo source of soluble RGD sequences is
fragments of ECM proteins such as collagen that are frequently generated following tissue injury (9). Type I collagen is
a likely candidate because it is the major ECM protein in cardiac tissue (2), and it contains seven RGD sequences per
molecule (1). However, it remains to be determined whether
integrin-mediated vascular responses to such soluble RGD peptides will
occur in the coronary circulation where collagen has been shown to be
degraded in response to myocardial infarction (7) and
cardiomyopathy (23). Because the control of blood flow
within a vascular bed is determined predominantly by the resistance
vessels, we deemed it important to understand the ability of
RGD-binding integrins to influence vascular tone in coronary resistance
arterioles. Specifically, we tested the hypothesis that
integrin-binding, RGD-containing peptides affect coronary microvascular
tone by interacting with the v3- and
51-integrins. To test this hypothesis, the effects of synthetic cyclic GPenGRGDSPCA (cyclic RGD), highly specific and novel v3- and
51-binding peptides (29,
32), and collagen fragments on isolated and pressurized coronary
resistance vessels were examined. Studies were also undertaken to
determine the involvement of endothelial versus smooth muscle integrins.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolated vessel preparation. The techniques for identification and isolation of pig coronary microvessels were described previously (14). Pigs (8-12 wk old of either sex) were anesthetized with pentobarbital sodium (20 mg/kg). After a left thoracotomy, the heart was electrically fibrillated, excised, and placed in cold (5°C) saline solution. The procedures followed were in accordance with guidelines set by the Laboratory Animal Care Committee at Texas A&M University. Each arteriole (60-130 µm in internal diameter in situ) was dissected from the subepicardium and then cannulated with physiological salt solution (PSS)-filled micropipettes in a Lucite vessel chamber. After cannulation of arterioles, the chamber was transferred to the stage of an inverted microscope (model IM35, Zeiss). Arterioles were bathed in PSS at 36.5°C and pressurized without flow at 60 cmH2O by a reservoir system to allow development of basal tone. Internal diameter of an arteriole was measured using video microscopic techniques, as described previously (13).
Experimental protocols.
After arterioles developed stable basal tone (~40 min) at 60 cmH2O, the concentration-diameter relationships for cyclic
RGD (0.2 µM-0.2 mM; GIBCO-BRL), GRGESP (0.2 µM-0.2 mM;
Life Technologies), an v3-cyclic-binding
peptide (XJ735, 0.07 µM-0.2 mM; DuPont Pharmaceuticals), an
51-binding peptide (DMP7677, 0.07-70
µM; DuPont Pharmaceuticals), and protease-generated (neutrophil
elastase) fragments of denatured collagen type I (0.2-4.0 µM)
were established. Peptides were added at 3-min intervals to the vessel
bath (abluminal addition) without causing fluctuations in temperature.
Purified rat-tail collagen type I (Becton-Dickinson) was dialyzed into PSS, and collagen fragments were prepared as described previously (22); the concentration of fragments was determined from
the molecular weight of intact collagen. We have previously shown (22) that the dilation of skeletal muscle arterioles to
collagen type I fragments can be inhibited after treatment with a
3-integrin function-blocking antibody (F11) and that
these fragments competitively interfere with the effects of RGD in a
cell binding assay. These findings strongly implicate an RGD-dependent
mechanism for the action of collagen fragments.
v3-
or 51-receptors in the vasomotor
responses to the integrin-binding peptides was addressed by
pretreatment for 15 min with function-blocking monoclonal antibodies
directed against either 3-integrins (clone F11; 100 µg; PharMingen) or 5-integrins (clone HM5-1;
50 µg; PharMingen). XJ735 and DMP7677 were then added to the vessel
bath to assess the blocking effects of the antibodies.
The role of endothelium in these vascular responses was evaluated by
comparing the response before and after endothelial removal. A
nonionic detergent,
3-[(3-cholamidopropyl)- dimethylammonio]-1-propanesulfonate (0.4%), was perfused into the arteriole to remove endothelial cells,
as reported previously (12). In another series of studies, the involvement of prostaglandins was examined by comparing the vascular responses before and after extraluminal incubation (30 min) of
arterioles with the cyclooxygenase inhibitor indomethacin (10 µM).
This treatment completely inhibited arachidonic acid-induced dilation
in our previous studies (10, 13).
To assess whether the observed vascular responses of coronary
arterioles to integrin peptides under luminal pressure also occur in
the presence of flow, cyclic RGD-mediated vasomotor responses were
examined in microvessels perfused with flow. Vascular response to
increased flow was studied under constant luminal pressure using
dual-reservoir techniques as demonstrated previously (15). In brief, the luminal flow was produced by simultaneously moving the
pressure reservoirs in opposite directions of the same magnitude, generating a pressure gradient of 10 cmH2O (mean volumetric
flow of ~7.5 nl/s) (15). Because we (10,
13) have previously demonstrated that flow induces
endothelium-dependent nitric oxide (NO)-mediated dilation in pig
coronary arterioles, the vascular response to cyclic RGD was studied in
perfused vessels pretreated with the NO synthase inhibitor
nitro-L-arginine methyl ester (L-NAME, 10 µM,
30 min). The cyclic RGD-mediated vascular response was also examined in
the L-NAME-pretreated vessels after incubation with
indomethacin (10 µM, 30 min).
Cyclic RGD, GRGESP, and DMP7677 were dissolved in PSS. Indomethacin and
XJ735 were dissolved in ethanol and 0.1 N HCl, respectively, as stock
solutions (10 mM). Subsequent concentrations of indomethacin and XJ735
were diluted in PSS. The final concentrations of ethanol and HCl in the
vessel bath were 0.1% and 0.01 N, respectively. Vehicle control
studies indicated that these solvent concentrations did not affect
arteriolar function.
Data analysis. At the end of each experiment, vessels with basal tone were relaxed with 100 µM sodium nitroprusside to obtain their maximal diameter at 60 cmH2O. All diameter changes in response to agonists were normalized to the vasodilation to 100 µM sodium nitroprusside and expressed as a percentage of maximal dilation. All data are presented as means ± SE. Statistical comparisons of vasomotor responses under various treatments were performed with ANOVA and tested with Fisher protected least significant difference test. Differences in resting diameter before and after pharmacological interventions were detected with Student's paired t-tests. Significance was accepted at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, all isolated coronary arterioles (n = 47) developed a similar level of basal tone (constricted to 66 ± 1% of maximal diameter) at 36.5°C bath temperature with 60 cmH2O intraluminal pressure without flow. The average
resting and maximal diameters of the vessels were 91 ± 3 and
137 ± 4 µm, respectively. The abluminal addition of cyclic RGD
to the vessel bath caused concentration-dependent vasodilation. Each
concentration of cyclic RGD produced vasodilation, which was developed
within 3 min, and the highest concentration (0.7 mM) elicited 90% of
maximal dilation (Fig. 1A). In
contrast, GRGESP, used as a negative control, did
not affect arteriolar diameter (Fig. 1A). We also examined
the effect of a highly specific v3-cyclic-binding peptide (XJ735) on
coronary arteriolar tone. XJ735 elicited concentration-dependent
vasodilation (Fig. 1B). The vasodilations to the cyclic
RGD and XJ735 were almost completely blocked by endothelial
removal and by the cyclooxygenase inhibitor indomethacin (10 µM)
(Fig. 1, A and B). Endothelial denudation did not
alter basal tone but did completely block vasodilation to
endothelium-dependent vasodilator bradykinin (1 nM) (12). Although the efficacy of the indomethacin concentration has been shown
previously (10, 13), we also observed here that a lower concentration of 2 µM indomethacin (n = 3, data not
shown) produced a similar inhibitory effect as with 10 µM
indomethacin on XJ735-mediated vasodilation without affecting basal
tone. Arteriolar dilations to the highest concentrations of
cyclic RGD and XJ735 were reduced to 18% by both treatments.
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The ability of another RGD-binding integrin,
51, to alter coronary arteriolar tone was
studied. A specific 51-binding peptide
(DMP7677) caused concentration-dependent dilation of coronary arterioles (Fig. 1C). In contrast to cyclic RGD and XJ735,
51 ligation with DMP7677 following
endothelial removal resulted in a concentration-dependent
vasoconstriction (Fig. 1C), which indicates a vascular
smooth muscle involvement. A comparable level of vasoconstriction to
DMP7677 was observed in another set of vessels after incubation with
indomethacin (Fig. 1C).
The specific involvement of the v3- and
51-integrins in mediating vasodilation to
the integrin-binding peptides was evaluated by pretreatment with
function-blocking monoclonal antibodies directed against either
3-integrins (F11) or 5-integrins
(HM5-1). The vasodilation to the
v3-cyclic-binding peptide XJ735 (21 µM) was significantly inhibited by F11 but not by HM5-1 (Fig.
2). The vasodilation to the
51-binding peptide DMP7677 (7 µM) was abolished by HM5-1, but was not altered by F11 (Fig. 2). The antibodies did not affect the vasodilation to sodium nitroprusside (data not shown) or the resting vessel diameter.
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The influence of flow on integrin-mediated vasodilation was examined in
isolated coronary arterioles in the presence of L-NAME (10 µM). In the absence of flow, coronary arterioles pressurized at 60 cmH2O dilated in a concentration-dependent manner to cyclic RGD. After washout of cyclic RGD, establishment of a pressure gradient
of 10 cmH2O elicited dilation in control vessels (i.e., control diameter, 88 ± 6 µm vs. flow diameter, 115 ± 9 µm, Fig. 3A).
L-NAME abolished the flow-induced vasodilation (flow + L-NAME diameter, 89 ± 7 µm, Fig. 3A). In
the presence of both flow and L-NAME, coronary arteriolar
dilation to cyclic RGD was maintained (Fig. 3B). However, as
in the nonperfused vessels (Fig. 1A), the cyclic
RGD-mediated dilation in the perfused vessels was inhibited by
indomethacin (10 µM, Fig. 3B). Indomethacin did not alter
the resting vessel diameter (88 ± 4 µm, Fig. 3A).
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A putative in vivo source of soluble RGD sequences is fragments of ECM
proteins that are frequently generated following tissue injury
(8). In support of this idea, protease-generated
(neutrophil elastase) fragments of denatured collagen type I (4 µM)
produced a robust dilation of an isolated arteriole from the baseline
diameter of 84 to 142 µm (Fig.
4A). The diameter gradually
returned to the baseline level after the vessel bath was replaced with
control solution (Fig. 4A). After removal of the
endothelium, vasodilation to collagen fragments (4 µM) was reduced
from 80 to 94 µm (Fig. 4B). The diameter returned to the
baseline level following washout, and then sodium nitroprusside
produced maximal dilation of the vessel from 82 to 146 µm (Fig.
4B). Further study showed that collagen fragments elicited
concentration-dependent vasodilation of endothelium-intact vessels
(Fig. 4C). In general, the vasodilation to each
concentration of collagen fragments was developed within 3-4 min,
and dilation to the highest concentration (4 µM) elicited 92% of
maximal dilation (Fig. 4C). The vasodilatory response was significantly inhibited by endothelial removal and by incubation with
indomethacin (Fig. 4C). Vasodilations to the highest
concentration under these conditions were reduced to 22% and 35% of
maximal dilation, respectively (Fig. 4C). It is important to
note that concentration-dependent vasodilation to sodium nitroprusside
(1 nM-10 µM) was not altered by either endothelial denudation or indomethacin (data not shown), which indicates that these treatments did not affect smooth muscle vasodilatory function.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study provides the first evidence that coronary
microvessels dilate in the presence of RGD-containing peptides. The
synthetic peptide cyclic RGD and novel
v3- and
51-binding peptides XJ735 and DMP7677
elicit dilations of isolated coronary arterioles by interaction with
integrin receptors on the endothelium. The endothelium-dependent
vasodilations appear to be mediated by activation of the cyclooxygenase
pathway because cyclooxygenase blockade inhibited the vasodilatory
responses. In a similar manner, neutrophil elastase-generated collagen
fragments produced endothelium-dependent, cyclooxygenase-mediated
dilation of these microvessels.
The tripeptide RGD is a target amino acid recognition sequence for many
integrins. Recent studies have shown that integrin-binding, RGD-containing peptides alter vasomotor tone in a variety of vascular preparations, including skeletal muscle (21, 22),
mesentery (17), kidney (34), and aorta
(17, 20, 28, 31). However, the influence of these
RGD-containing peptides on the coronary circulation has not been
examined. In the present study, ligation of
v3 or 51
produced dilation of isolated and pressurized porcine coronary
arterioles. Because this vasodilatory response was almost completely
blocked by endothelial removal, it is suggested that the vasodilation
is mediated by activation of endothelial integrins. This finding is
consistent with those reported in the rat aorta (20, 31).
In contrast, Mogford et al. (22) previously demonstrated
that the cyclic RGD peptide elicits endothelium-independent dilation of
rat skeletal muscle microvessels. These disparate results suggest that
the mechanisms of integrin-mediated control of vascular tone vary with
the vascular tissue studied.
RGD-containing peptides have been shown to bind to various integrins,
including v3,
v5, v8, and
51 (27). Because the
RGD-containing peptides used in previous studies are nonselective, the
possibility that multiple integrins may be involved cannot be ruled
out. To overcome this specificity problem, we utilized two novel
compounds, XJ735 and DMP7677, which are selective for binding
v3 (29) and
51 (32) receptors,
respectively. Both of these compounds produced concentration-dependent
dilation of coronary arterioles. Activation of the selective
v3- and
51-receptors was confirmed by the ability
of a 3-function-blocking antibody to inhibit the
vasodilation to XJ735 and an 5-function-blocking antibody to abolish the vasodilation to DMP7677. After removal of the
endothelium, vasodilation to XJ735 was almost completely blocked,
whereas the vasodilatory response to DMP7677 was reversed to
concentration-dependent vasoconstriction. Taken together, these results
suggest that activation of endothelial
v3- and
51-receptors can elicit coronary
arteriolar dilation. In addition, the
51-receptor-dependent vasodilation
appears to override a vasoconstrictor response to smooth muscle
51-receptors. In smooth muscle cells from
rat cremaster arterioles, electrophysiological evidence suggests that coupling between the 51-integrin and
L-type Ca2+ channel results in enhanced Ca2+
entry (33). This selective integrin-signaling mechanism is consistent with the vasoconstriction observed in the present study.
The activation of endothelial v3- and
51-receptors may stimulate the production
and release of endothelium-derived vasodilators. Previous studies have
shown that RGD-containing peptides evoke endothelium-dependent
vasodilation via release of NO (17, 31) or of
prostaglandins (17). In the present study, administration of indomethacin to the coronary arterioles, with a concentration (10 µM) sufficient to block prostaglandin synthesis in our previous studies (10, 13), inhibited the vasodilations to cyclic
RGD, XJ735, and DMP7677 to the same extent as did endothelial removal. This result indicated that v3- and
51-induced vasodilations are mediated by
the endothelial release of prostaglandins. Our conclusion is supported
by evidence showing that fibrin interaction with the
v3-integrin on human umbilical vein
endothelial cells increases release of a prostaglandin prostacyclin
(5). However, it is important to note that the
integrin-mediated vasodilatory response of pig coronary microvessels is
different from that in rat skeletal muscle microvessels, which is
induced by smooth muscle v3-integrins
(22) linked to potassium channels (25) and the L-type Ca2+ channel (33). Despite the
possible species or tissue differences, it appears that activation of
the cyclooxygenase pathway in coronary arterioles is responsible for
the endothelium-dependent component of vasodilation to the nonspecific
cyclic RGD and specific v3- and
51-binding peptides.
A potential caveat of our findings is that the isolated microvessels were studied in the absence of flow, a condition that would not occur in the heart in vivo. Thus we studied the coronary arteriolar response to cyclic RGD in the presence of flow. To study the RGD-mediated response in the presence of flow, we had to abolish the flow-mediated dilation in coronary arterioles to preserve vascular tone. This NO-dependent vasodilatory response was blocked by incubating the vessels with L-NAME, which is consistent with results reported in our previous studies (10, 13). In addition, these perfused vessels dilated in response to abluminal cyclic RGD in the same fashion as those in the nonperfused vessels, suggesting a physiological relevance of the observed vasomotor responses. Importantly, because the impaired coronary flow regulation observed in patients with heart disease has been suggested to be a result of NO deficiency (26, 35), the integrin-binding peptides (XJ735 and DMP7677) could be used clinically to ameliorate vascular function by providing an alternative form of coronary vasodilation through the release of prostaglandins.
Physiological mediators for the activation of integrin receptors in the
vasculature may be fragments of ECM proteins, such as collagen, that
are frequently generated following tissue inflammation and injury
(8). The binding of specific integrins to collagen is
recognized to change following conversion of collagen from its native
state to a denatured condition (8). This is proposed to
result from exposure of cryptic RGD sequences (matricryptic sites)
(9). Subsequent proteolytic cleavage of the denatured collagen by enzymes of tissue and inflammatory cell origin may release
soluble RGD-containing fragments or matricryptins (9). Indeed, neutrophil elastase-generated collagen fragments bind v3-receptors to elicit dilation of rat
skeletal muscle microvessels in an RGD-dependent fashion
(22). In our present study, these collagen fragments
dilated coronary arterioles in a concentration-dependent manner.
Because this vasodilation was significantly inhibited by endothelial
removal and by indomethacin, it is suggested that activation of
endothelial integrins and subsequent release of prostaglandins are
involved in mediating this vasodilatory response. The inability of
these treatments to completely block the collagen fragment-induced
vasodilation, as well as the integrin peptide-induced vasodilations
described above, indicates that smooth muscle integrins may also be
involved in vasodilation to higher concentrations of these
fragments/peptides. On the other hand, it is possible that the release
of other endothelium-derived relaxing factors such as
endothelium-derived hyperpolarizing factor is involved in the residual
vasodilations. An involvement of NO is not supported by our data
because the vasodilation at higher concentrations persisted in the
L-NAME-pretreated perfused microvessels. Regardless of
these interpretations, because collagen degradation is associated with
a number of coronary complications such as atherogenesis (19), myocardial infarction (7), and
cardiomyopathy (23), our current data indirectly support
the hypothesis that fragments of ECM proteins may act as wound
recognition signals and play a role in the vascular response to these
pathologies. However, the rate and formation of such vasoactive matrix
fragments remains to be determined.
It is important to note that type I collagen is not a major basement membrane component of blood vessels like type IV collagen (1). However, because type I collagen is the major ECM protein in the heart (2), it could be a major source of RGD for coronary microvessels. This is not to underestimate the involvement of basement membrane collagen type IV. However, in the present study, the application of collagen type I fragments or integrin-binding peptides to the vessel bath mimics the abluminal exposure of microvessels to these peptides derived from the interstitial space of the heart. Interestingly, we have estimated the concentration of collagen type I fragments in the interstitial space of the heart using data reported in the literature. Our calculations are as follows. The wet weight of pig hearts used in our studies was ~100 g. The heart dry weight, which has been reported to be ~20% of the wet weight, would be 20 g (16). Because the collagen content of the myocardium has been shown to be ~4.0% of the heart dry weight (16), the pig heart would contain ~0.8 g of total collagen. It is estimated that 0.7 g of collagen are type I collagen in the pig heart because type I collagen constitutes 85-90% of myocardial collagen (2). The fraction of collagen that undergoes extracellular degradation daily in the heart has been reported to be ~2.5% (18). This would produce 18 mg of degraded collagen fragments in the interstitial space (interstitial fluid volume = 20 ml because interstitial fluid volume has been reported to be 20% of heart wet weight) (2, 6). Thus it is possible that 0.9 mg/ml of collagen type I fragments are present in the interstitial fluid under normal conditions. This level of collagen fragments is nearly equivalent to the highest concentration of collagen fragments used in our study (1 mg/ml = 4 µM), which could provide numerous RGD-binding sites because type I collagen contains 7 RGD sequences per molecule (1). Interestingly, the concentration of collagen fragments are probably even much higher under conditions of myocardial infarction, where the collagen content has been shown to be degraded by as much as 25-50% (4, 30). Thus the experimental design of our study allowed us to assess the effect of a physiological level (i.e., representative of myocardial interstitium) of collagen type I fragments on vasomotor function in isolated coronary arterioles. Future studies will investigate in vivo evidence for the influence of collagen type I degradation products on coronary microvascular tone.
In conclusion, the present study demonstrates that selective
v3- and
51-peptides XJ735 and DMP7677 elicit
dilations of isolated coronary microvessels. It appears that these
vasodilatory responses are a result of the compounds binding
endothelial v3- and
51-receptors and subsequent production of
cyclooxygenase-derived prostaglandins. RGD-containing peptide cyclic
RGD and protease-generated collagen fragments also induce
endothelium-dependent prostaglandin-mediated dilations of these
microvessels. Collectively, these data support a role for endothelial
integrins in the regulation of vascular tone in the coronary circulation.
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ACKNOWLEDGEMENTS |
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G. A. Meininger is supported by National Heart, Lung, and Blood Institute (NHLBI) Grants HL-55050 and HL-58810. L. Kuo is supported by NHLBI Grants HL-55524, HL-48179, and HL-03693.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. A. Meininger, Cardiovascular Research Institute, Dept. of Medical Physiology, College of Medicine, Texas A&M Univ. System Health Science Center, College Station, TX 77843-1114 (E-mail address: gam{at}tamu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12 April 2001; accepted in final form 17 August 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05, all
interventions vs. endothelium intact.
