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Am J Physiol Heart Circ Physiol 289: H322-H329, 2005. First published February 18, 2005; doi:10.1152/ajpheart.00923.2003
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{alpha}v{beta}3- and {alpha}5{beta}1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles

Luis A. Martinez-Lemus, Tracy Crow, Michael J. Davis, and Gerald A. Meininger

Department of Medical Physiology, Cardiovascular Research Institute, Division of Vascular Biology, Texas A&M University System Health Science Center, College Station, Texas

Submitted 29 September 2003 ; accepted in final form 16 February 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
In isolated resistance arterioles with spontaneous tone, ligation of {alpha}4{beta}1- and {alpha}5{beta}1-integrins induces vasoconstriction whereas ligation of {alpha}v{beta}3-integrin induces vasodilation. However, whether integrins directly participate in myogenic constriction to pressure elevation is not known. To answer this question, isolated rat skeletal muscle arterioles were exposed to step increments in pressure in the absence or presence of peptides and function-blocking antibodies known to bind {alpha}4{beta}1-, {alpha}5{beta}1-, or {alpha}v{beta}3-integrins while vessel diameter was continually monitored. Myogenic constriction, as assessed by the ability of isolated arterioles to reduce their diameter in response to two consecutive increments in intraluminal pressure (90–110 and 110–130 cmH2O), was not affected by treatment with any of the control peptides (RAD, LEV), a control antibody (anti-rat major histocompatibility complex), an {alpha}4{beta}1-integrin-binding peptide (LDV), or an anti-{alpha}4-integrin antibody. In contrast, {alpha}5{beta}1-integrin blockade with either anti-{alpha}5- or anti-{beta}1-integrin antibody caused a significant inhibition of myogenic constriction. Also, both RGD peptide and anti-{beta}3-integrin antibody inhibited myogenic constriction. These results indicate that {alpha}5{beta}1- and {alpha}v{beta}3-integrins are necessary for myogenic constriction and further suggest that integrins are part of the mechanosensory apparatus responsible for the ability of vascular smooth muscle cells to detect and/or respond to changes in intraluminal pressure.

mechanosensors; spontaneous tone; autoregulation; mechanotransduction; microcirculation

MYOGENIC BEHAVIOR in blood vessels is characterized by the development of vasoconstriction in response to intraluminal pressure elevation, the maintenance of basal myogenic tone, and vasodilation in response to pressure reduction. The primary functions of myogenic behavior include autoregulation of blood flow and regulation of capillary hydrostatic pressure, which may be affected in a variety of vascular disorders including those encountered in hypertension, diabetes, and aging (16, 19, 28, 35, 44). Myogenic behavior is independent of neuronal and hormonal mechanisms and occurs in the absence of endothelium (9, 11, 20). Therefore, it is considered an intrinsic characteristic of the blood vessel wall, with vascular smooth muscle as the primary effector responsible for the phenomenon.

Significant progress is being made toward identifying the mechanisms responsible for all classes of myogenic behavior including myogenic vasoconstriction, the maintenance of basal myogenic tone, and myogenic vasodilation (9, 11, 15, 20, 36). Conceptually, changes in pressure are detected by a mechanosensory apparatus in vascular smooth muscle and subsequently transduced to changes in contractile activation and/or actin polymerization. Numerous cell signals such as ion channels (9), intracellular calcium (5, 29, 55, 56), RhoA-Rho kinase (3, 15, 53), protein kinase C (18, 46, 50), and arachidonic acid derivatives (4, 12, 13) have been shown to be active participants in myogenic behavior. Although some cellular mechanisms appear to be needed in all classes of myogenic behavior, others predominate in or appear to be exclusive to one phase. However, the elements involved in sensing/transducing wall tension or stress as produced by intraluminal pressure have not been identified.

Because of the capacity of integrins to link the extracellular matrix to focal contact signaling proteins and the cytoskeleton, these heterodimeric transmembrane proteins have received serious consideration as links for transmission of force from the extracellular matrix into the cell. As such, they may play a pivotal role in mediating vascular myogenic behavior (11, 26). Furthermore, integrins are capable of transmitting signals across the "extracellular matrix-integrin-cytoskeletal axis" in both directions (14), which makes them ideal candidates for mechanosensors.

To test the hypothesis that integrins are essential components in the mechanism(s) responsible for myogenic behavior, the present study compared the effects of {alpha}5{beta}1-, {alpha}4{beta}1-, or {alpha}v{beta}3-integrin blockade on the myogenic constriction of isolated arterioles induced by step increments in intraluminal pressure. These specific integrins were selected because previous reports showed that their ligation affects vascular smooth muscle intracellular calcium and modifies vascular diameter.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. This study followed institutional guidelines and was approved by the Texas A&M University Animal Use and Care Committee for all procedures involving animals. Male Sprague-Dawley rats (Harlan, Houston, TX) with body weights ranging from 250 and 350 g were used in the study. Anesthesia was achieved in all rats via an intraperitoneal injection of pentobarbital sodium (100 mg/ml).

Vessel isolation. After a surgical plane of anesthesia was confirmed, the right cremaster muscle was excised and pinned flat in a refrigerated (4°C) Lexan dissecting chamber that contained a physiological saline solution (PSS) of the following composition (in mM): 145.0 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, 1.0 NaH2PO4, 5.0 dextrose, 3.0 MOPS buffer, 2.0 pyruvate, 0.02 EDTA, and 0.15 BSA (Amersham Life Sciences, Arlington Heights, IL), pH 7.4. The tissue remained in the cold environment for 60 min of equilibration. A segment of the cremaster first-order feed arteriole was isolated, cannulated without flow, and pressurized to 90 cmH2O within an observation chamber filled with PSS (without albumin) as previously described (39). The cannulated arteriole was transferred to the stage of an inverted microscope (Zeiss IM35), where lumen diameter was recorded online with a calibrated video caliper system connected to a video camera and monitor. Only vessels that spontaneously developed basal tone were included in the study.

Peptide and antibody treatments. All peptides and antibodies were diluted in PSS and added abluminally to the arterioles in the bath. Arterioles were pretreated for 15 min before a series of pressure increments was performed to determine the effect of the treatment on myogenic constriction (see Experimental protocols). The RGD-containing peptide GRGDSP (glycine-arginine-glycine-aspartate-serine-proline; Bachem) was used at three concentrations (21, 70, and 210 µM) previously shown to induce vasodilation in isolated skeletal muscle arterioles (32). The RAD-containing peptide GRADSP (glycine-arginine-alanine-aspartate-serine-proline; Biomol) was used as a control peptide in the RGD experiments at a concentration of 210 µM. The LDV-containing peptide EILDVSPT (glutamate-isoleucine-leucine-aspartate-valine-serine-proline-threonine; Peninsula Labs) was used at a concentration (210 µM) previously shown to induce vasoconstriction in isolated skeletal muscle arterioles (48). The LEV-containing peptide EILEVSPT (glutamate-isoleucine-leucine-glutamate-valine-serine-proline-threonine; Peninsula Labs) was used as a control peptide in the LDV experiments at a concentration of 210 µM.

Vascular smooth muscle integrins were blocked with the following antibodies: 50 µg/ml of the anti-{beta}3-integrin function-blocking antibody F11 (Pharmingen), 50 µg/ml of the anti-{beta}1-integrin function-blocking antibody Ha2/5 (Pharmingen), 100 µg/ml of the anti-{alpha}5-integrin function-blocking antibody HM{alpha}5–1 (Pharmingen), and 100 µg/ml of the anti-{alpha}4-integrin function-blocking antibody MR{alpha}4–1 (Pharmingen); 50 µg/ml of the anti-rat major histocompatibility complex (MHC) class I monoclonal antibody was used as a control (clone R4-8B1, Seikagaku America). All concentrations refer to final concentrations in the vessel bath.

Experimental protocols. All experimental protocols were initiated in vessels that developed spontaneous basal tone after 1 h of equilibration at 34.5°C and 90 cmH2O of intraluminal pressure. First, a series of step increments in intraluminal pressure to 110 and 130 cmH2O was performed at 10-min intervals, and the new diameters were recorded once the vessel had stabilized at each new pressure. Intraluminal pressure changes were achieved by adjusting the height of a reservoir that supplied the intraluminal buffer through the open pipette on which the vessel was cannulated. After the first series of pressure increments, the vessel was returned to 90 cmH2O and allowed to stabilize for 15 min. Once the vessel had returned to its original diameter at 90 cmH2O, it was incubated for 15 min with one of the peptides or antibodies. A second series of step increments in pressure was then performed in the presence of the peptide or antibody. The vessel was then returned to a pressure of 90 cmH2O and washed with fresh PSS without the peptide or antibody for 15 min. A representative tracing of these series of changes in pressure is shown in Fig. 1. To conclude the experiment the vessel was dilated with 100 µM adenosine, followed by calcium-free PSS containing 100 µM adenosine to obtain the maximal passive diameter. Arteriolar diameter changes to peptides, antibodies, and pressure were quantified as a percentage of the initial arteriolar diameter with basal spontaneous tone at 90 cmH2O. The internal diameter of all vessels studied (n = 64) was 102 ± 1.9 µm (61.2 ± 1.2% of passive diameter) after the development of basal spontaneous tone. Maximal passive diameter was 168 ± 2.6 µm.



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  		Fig. 1. Representative tracing showing the effect of changes in intraluminal pressure on arteriolar diameter occurring in the absence or presence of an anti-{beta}3-integrin function-blocking antibody.

 
Data analysis. All data are expressed as means ± SE. Linear regression analysis was performed on the diameter values for each of the pressure step series as previously described (13). Isolated skeletal muscle arterioles from the rat cremaster respond with constriction to increments in intraluminal pressure within the physiological range used in the present experiments (5, 29). Thus myogenic constriction is represented by a negative slope of the pressure vs. diameter regression line and defines the ability of the isolated arterioles to reduce their diameter in response to intraluminal pressure increments. Differences between the slopes of the regression lines were determined with ANOVA followed by Fisher's protected least significant difference comparison of the means. Analyses of the slopes and diameter responses to peptide or antibody treatment within the same vessel were performed with repeated-measures ANOVA. In all statistical analyses a P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
In the absence of antibody or peptide treatment, all arterioles responded with vasoconstriction in response to the step increments in pressure, which resulted in a negative slope of the pressure vs. diameter regression line (–0.27 ± 0.01; n = 64). As previously reported (4), myogenic constriction in the same arteriole was highly reproducible during the second series of step increments in intraluminal pressure and was not affected by treatment with either the control peptides (LEV, RAD) or the control antibody (anti-rat MHC type I). All arterioles also responded with vasodilation as the intraluminal pressure was decreased from 130 cmH2O back to the original 90 cmH2O.

As myogenic constriction has been associated with an increase in intracellular calcium concentration (15, 29), and as both {alpha}5{beta}1- and {alpha}4{beta}1-integrins have been shown to enhance basal tone of isolated arterioles as well as L-type calcium current in isolated vascular smooth muscle cells (31, 48, 51, 52), we first performed a series of experiments aimed at determining whether or not blocking these integrin receptors would inhibit myogenic constriction. Blockade of {alpha}5{beta}1-integrin was achieved via the abluminal incubation of arterioles with either anti-{alpha}5-integrin or anti-{beta}1-integrin function-blocking monoclonal antibodies. Although blockade of {beta}1-integrin caused no significant changes in basal tone, {alpha}5-integrin blockade induced vasodilation (from 55 ± 3% to 66 ± 3% of passive diameter, n = 13; Fig. 2A), but blockade of either integrin resulted in a significant inhibition of myogenic constriction compared with that observed in the same arterioles before the addition of the antibodies and that observed during treatment with the control anti-rat MHC class I antibody (Fig. 2B). The involvement of {alpha}4{beta}1-integrin in myogenic constriction was determined by two different approaches. One approach consisted of abluminally applying a peptide containing the {alpha}4{beta}1-integrin-binding sequence LDV at a concentration known to increase vascular smooth muscle intracellular calcium and cause vasoconstriction (48). The second approach consisted of blocking vascular smooth muscle {alpha}4{beta}1-integrin receptors via the abluminal application of an anti-{alpha}4-integrin function-blocking antibody (48). Addition of LDV peptide caused a significant vasoconstriction (from 57 ± 2% to 43 ± 1% of passive diameter, n = 4; Fig. 3A). However, no significant change in myogenic constriction was elicited by the presence of LDV peptide in the bath compared with the myogenic constriction observed in the same arterioles before the addition of LDV or that observed in other arterioles after treatment with the control peptide LEV (Fig. 3B). Abluminal application of the function-blocking anti-{alpha}4-integrin antibody induced a significant vasodilation (from 58 ± 1% to 67 ± 2% of passive diameter, n = 4; Fig. 3C), but, as with LDV peptide, blockade of {alpha}4{beta}1-integrin with the anti-{alpha}4-integrin antibody did not cause any significant changes in myogenic constriction (Fig. 3D).



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  		Fig. 2. A: % control diameter of isolated arterioles exposed to step increments in intraluminal pressure before and after abluminal treatment with a control antibody anti-rat major histocompatibility complex (MHC), an anti-{alpha}5-integrin function-blocking antibody, or an anti-{beta}1-integrin function-blocking antibody. B: slope of the myogenic response as determined by the regression analyses of the changes in vessel diameter occurring in response to step increments in pressure before the addition of antibody (untreated, n = 21) and while in the presence of the control anti-MHC (n = 4), the anti-{alpha}5-integrin antibody (n = 13), or the anti-{beta}1-integrin antibody (n = 4). Data are means ± SE. *Significantly different from control (anti-MHC).

 


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  		Fig. 3. A: % control diameter of isolated arterioles exposed to step increments in intraluminal pressure before and after abluminal treatment with either a control peptide containing the LEV sequence or the {alpha}4{beta}1-integrin binding peptide containing the LDV sequence. B: slope of the myogenic response as determined by regression analyses of the changes in vessel diameter occurring in response to step increments in pressure before the addition of peptide (untreated, n = 8) and while in the presence of the control LEV (n = 4) or the {alpha}4{beta}1-integrin binding peptide LDV (n = 4). Data are means ± SE. C: % control diameter of isolated arterioles exposed to step increments in intraluminal pressure before and after abluminal treatment with either a control antibody anti-rat MHC or an anti-{alpha}4-integrin function-blocking antibody. D: slope of the myogenic response as determined by regression analyses of the changes in vessel diameter occurring in response to step increments in pressure before the addition of antibody (untreated, n = 8) and while in the presence of the control anti-MHC (n = 4) or the anti-{alpha}4-integrin (n = 4) antibody. Data are means ± SE.

 
In contrast to the enhanced spontaneous tone observed on ligation of {alpha}5{beta}1- and {alpha}4{beta}1-integrins, binding of {alpha}v{beta}3-integrin by RGD-containing peptides elicits a sustained vasodilation of isolated skeletal muscle resistance arterioles (32). As with {alpha}4{beta}1-integrin, we took two approaches to determine the involvement of {alpha}v{beta}3-integrin in myogenic constriction. First, we abluminally applied increasing concentrations of an {alpha}v{beta}3-integrin-binding peptide containing the RGD sequence to the isolated arterioles and determined its effect on basal tone as well as on myogenic constriction. The second approach consisted of blocking vascular smooth muscle {alpha}v{beta}3-integrin receptors via the abluminal application of an anti-{beta}3-integrin function-blocking antibody. Addition of RGD peptide caused a concentration-dependent vasodilation (from 66 ± 2% to 71 ± 2%, from 57 ± 2% to 63 ± 2%, and from 62 ± 2% to 72 ± 2% of passive diameter for 21, 70, and 210 µM RGD, respectively; n = 6 for each concentration; Fig. 4A) and a significant inhibition of myogenic constriction at all concentrations compared with myogenic constriction observed in the same arterioles before the addition of RGD or that observed in other arterioles after treatment with the RAD control peptide (Fig. 4B). Blockade of {alpha}v{beta}3-integrin with the anti-{beta}3-integrin function-blocking antibody also inhibited myogenic constriction (Fig. 4D) but caused no significant changes in basal tone (Fig. 4C). Addition of the RAD control peptide did not cause any significant changes in basal tone or myogenic constriction.



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  		Fig. 4. A: % control diameter of isolated arterioles exposed to step increments in intraluminal pressure before and after abluminal treatment with either a control peptide containing the RAD sequence or the integrin-binding peptide containing the RGD sequence at 3 concentrations, 21, 70, and 210 µM. B: slope of the myogenic response as determined by regression analyses of the changes in vessel diameter occurring in response to step increments in pressure before the addition of peptide (untreated, n = 18) and while in the presence of the control RAD (n = 6) or the 3 concentrations of the RGD peptide (n = 6 for each concentration). Data are means ± SE. *Significantly different from control (RAD). C: % control diameter of isolated arterioles exposed to step increments in intraluminal pressure before and after abluminal treatment with either a control antibody anti-rat MHC or an anti-{beta}3-integrin function-blocking antibody. D: slope of the myogenic response as determined by the regression analyses of the changes in vessel diameter occurring in response to step increments in pressure before the addition of antibody (untreated, n = 11) and while in the presence of the control anti-MHC (n = 4) or the anti-{beta}3-integrin (n = 7) antibody. Data are means ± SE. *Significantly different from control (anti-MHC).

 
Finally, to determine whether integrin blockade had any effect on vasoconstrictor stimuli other than pressure elevation, a series of vessels were exposed to either norepinephrine (10–5.5 M) or KCl (70 mM) while in the presence of anti-{alpha}5-integrin or anti-{beta}3-integrin function-blocking antibody. Although both the anti-{alpha}5-integrin and anti-{beta}3-integrin antibodies inhibited myogenic constriction, their presence did not affect the constriction elicited by either norepinephrine or KCl. Norepinephrine caused constriction from 76 ± 8% to 31 ± 7% of passive diameter (n = 4), and KCl caused constriction from 89 ± 10% to 45 ± 9% of passive diameter (n = 4). In two series of vessels, vasoconstriction with norepinephrine (10–5.5 M) was induced before and after incubation with the anti-{alpha}5-integrin and anti-{beta}3-integrin antibodies. Vasoconstriction to norepinephrine was not affected by the presence of either antibody. Vessels constricted to 23.2 ± 2.6% and 24.1 ± 3.1% of passive diameter before and after incubation with anti-{alpha}5-integrin (n = 4), respectively, and constricted to 17.4 ± 2.0% and 16.2 ± 2.2% of passive diameter before and after incubation with anti-{beta}3-integrin (n = 4), respectively.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study provides evidence that {alpha}5{beta}1- and {alpha}v{beta}3-integrins are directly involved in the mechanisms underlying vascular myogenic behavior. Function-blocking anti-{alpha}5-integrin or anti-{beta}1-integrin antibodies significantly inhibited the capacity of arterioles to constrict in response to increments in intraluminal pressure, thus indicating that {alpha}5{beta}1-integrin is required for myogenic constriction. Myogenic constriction was also inhibited by an RGD peptide that preferentially affects {alpha}v{beta}3-integrin, and by an anti-{beta}3-integrin function-blocking antibody, thus indicating that {alpha}v{beta}3-integrin is also needed for myogenic constriction. In contrast, neither ligation nor blockade of {alpha}4{beta}1-integrin by an LDV peptide or an anti-{alpha}4-integrin antibody inhibited myogenic constriction, although both treatments significantly affected basal tone.

The first experimental evidence indicating that integrins may be active participants in the acute control of vascular diameter and myogenic behavior came from observations showing that, in isolated skeletal muscle arterioles, synthetic peptides containing integrin-binding amino acid sequences cause either vasodilation through {alpha}v{beta}3-integrin ligation or vasoconstriction through {alpha}4{beta}1-integrin and {alpha}5{beta}1-integrin ligation (6, 31, 32, 48). Further evidence indicated that integrin modulation of L-type calcium current in vascular smooth muscle cells is a primary mechanism by which integrin ligation modulates vascular diameter (48, 51, 52). Although evidence indicates that voltage-gated calcium channels and L-type calcium current modulation are required for myogenic constriction and basal tone (9, 11, 20), some studies suggest that the signaling pathways underlying the calcium increase in both the pressure-induced myogenic constriction and the integrin-mediated calcium influx may be independent (11, 26, 32). These results include the observations that 1) dilation of resistance arterioles in response to integrin-binding RGD peptides also occurs in vessels with no spontaneous basal tone that are preconstricted with norepinephrine or angiotensin (24, 32, 43); 2) vasoconstrictions induced by pressure and integrin ligands are additive in renal afferent arterioles (54); and 3) the enhanced L-type calcium current associated with {alpha}4{beta}1-integrin and {alpha}5{beta}1-integrin ligation is protein kinase C independent in isolated vascular smooth muscle cells (48, 51), whereas myogenic constriction can be blocked by protein kinase C inhibitors (18, 46, 50). These observations suggest that integrins may be modulating vascular tone via L-type calcium current modification without being directly involved in myogenic constriction. Our results, however, indicate that although this may be the case for {alpha}4{beta}1-integrin, the mechanisms underlying myogenic constriction require both {alpha}5{beta}1- and {alpha}v{beta}3-integrins.

L-type calcium channels play an obligatory role in the myogenic constriction of most blood vessels (9), and those channels can potentially be directly gated by stretch (23, 25). Whether they can be directly regulated by physiological levels of stretch remains a debated issue (9). To the contrary, the majority of electrophysiological evidence suggests that stretch-induced calcium entry through L-type calcium channels in vascular smooth muscle is secondary to the depolarization resulting from activation of a nonselective cation channel (8, 10, 49) or a chloride channel (33) or inhibition of potassium channels (17, 21). The present study does not exclude the involvement of these mechanisms or the possibility that {alpha}5{beta}1- and {alpha}v{beta}3-integrins may mediate stretch activation of the various other ion channels. Therefore, it is possible that vascular smooth muscle stretch directly modulates L-type calcium channel gating through integrin-mediated signaling while depolarization alters open probability of the channel through well-established mechanisms (34). It would be difficult to directly distinguish between these various possibilities with isolated vessel preparations because myogenic constriction and tone are almost completely sensitive to L-type channel inhibition.

Recent evidence also indicates that although the development of basal tone and myogenic constriction at an initial threshold in pressure is dependent on L-type channel activity and large increments in intracellular calcium, myogenic constriction in response to further elevation in transmural pressure is accomplished with comparatively small changes in membrane potential and intracellular calcium via processes associated with calcium sensitization (22, 36, 45). In light of the difference in cellular pathways controlling basal tone and myogenic constriction, it has been proposed that myogenic behavior be partitioned into three phases (36). The first phase consists of the development of tone, which is associated with large increments in intracellular calcium. The second phase, termed "myogenic reactivity," represents the constriction to a further increment in pressure. This phase, which is the phase examined in the present study, is largely dependent on calcium sensitization mechanisms and is referred to, in this study, as myogenic constriction. The third phase comprises forced dilation, when the vessel is no longer capable of constricting or maintaining diameter in response to pressure elevation. Furthermore, the constriction observed in response to pressure elevation within the myogenic reactivity phase may be divided into two stages controlled by different mechanisms, one responsible for the initial process of constriction and one responsible for the maintenance of the new diameter over time (4). The complexity and multiplicity of processes involved in myogenic behavior may explain why inhibition or stimulation of {alpha}4{beta}1-integrin causes changes in basal tone via L-type channel modulation (48), while having no effect in myogenic constriction. Similarly, differences in the mechanisms responsible for maintaining basal tone and myogenic constriction may account for the observation that blockade of {alpha}v{beta}3-integrin inhibited myogenic constriction without affecting basal tone, whereas blockade of {alpha}5{beta}1-integrin with anti-{alpha}5-integrin antibody caused significant changes in basal tone in addition to inhibiting myogenic constriction. Because integrins modulate a number of intracellular kinases (26, 30) in addition to modulating L-type calcium current in vascular smooth muscle cells, the possibility that integrin signaling may influence myogenic constriction via kinases that affect calcium sensitization should be considered.

Direct involvement of {alpha}5{beta}1- and {alpha}v{beta}3-integrins in myogenic constriction gives support to the possibility that these integrins may act as mechanosensors responsible for detecting the mechanical forces linked to changes in intraluminal pressure. The precise mechanism by which integrins may detect mechanical force is not known, but several ideas have been proposed (26). One possibility is that changes in intraluminal pressure cause a conformational change (unfolding) of extracellular matrix proteins that in turn expose new (cryptic) binding sites for integrins (7, 26). Binding of these newly exposed cryptic sites would in turn trigger an intracellular signaling cascade similar to that reported to occur on integrin ligation in isolated vascular smooth muscle cells (48, 51, 52). Another possibility is that integrins directly sense the force generated by the stretch of the vascular wall in response to changes in intraluminal pressure. Force then would be transmitted across the extracellular-integrin-cytoskeleton axis, initiating a signaling cascade to modulate myogenic constriction in a process comparable to the intracellular calcium increase and tyrosine phosphorylation occurring on integrin-specific mechanical stressing of isolated osteoblastic cells (40, 42).

{alpha}5{beta}1-Integrin is an integrin constitutively present in vascular smooth muscle, with an apparent predilection for insoluble ligands (26, 51, 52). Ligation of this integrin has been shown to enhance basal tone in isolated arterioles as well as L-type calcium current in isolated vascular smooth muscle cells (31, 51, 52). If the mechanism for detection of an intraluminal pressure increase results from exposure of cryptic sites in extracellular matrix proteins as those proteins unfold in response to vessel stretch, then unbound {alpha}5{beta}1-integrins in vascular smooth muscle cells would be available to bind the newly exposed cryptic sites, enhancing L-type calcium current to induce vasoconstriction. Blockade of myogenic constriction by anti-{alpha}5-integrin and anti-{beta}1-integrin antibodies is congruent with this scenario, as the antibodies would block free integrins on the cell membrane, preventing them from binding the newly exposed cryptic sites. Another possibility is that the antibodies interact with bound integrins through a competitive process causing a selective loss of {alpha}5{beta}1-integrin-matrix adhesions. Consequently, a mechanical stimulus would no longer be sensed whether transmission was through increased availability of new matrix binding sites or mechanical stressing of existing sites. The antibodies used for blocking {alpha}5- and {beta}1-integrins in the present study were previously shown to block specific cellular responses associated with ligation of {alpha}5{beta}1-integrin in rat isolated arterioles and isolated vascular smooth muscle cells (27, 31, 41, 52). Furthermore, we have shown (47) that these antibodies specifically block extracellular adhesion of fibronectin and RGD peptide to isolated vascular smooth muscle cells with atomic force microscopy. The specific epitope and the capacity of each antibody to compete with already established extracellular matrix-integrin interactions are not known and may contribute to the different effects of each individual antibody on basal tone. It is clear, however, that blockade of {alpha}5{beta}1-integrin with either antibody inhibited myogenic constriction. Further studies will be required to discriminate between the different possibilities by which integrins may be sensing changes in transmural pressure and affecting myogenic behavior.

In contrast to {alpha}5{beta}1-integrin, binding of {alpha}v{beta}3-integrin has been associated with vasodilation and reduction in L-type calcium current in vascular smooth muscle (6, 32, 52). The only integrin heterodimer including the {beta}3-subunit in vascular smooth muscle is {alpha}v{beta}3-integrin (26), and specific blockade of this integrin, with the same antibody used in the present study, has been shown to block the vasodilation induced by cyclic RGD peptides and fragments of collagen type I in isolated arterioles (6, 32). Thus it might be anticipated that blockade of {alpha}v{beta}3-integrin would induce enhancement of myogenic constriction. In contrast to this, it was observed that blockade of {alpha}v{beta}3-integrin inhibited myogenic constriction. Several possibilities exist as to how blockade of {alpha}v{beta}3-integrin may be inhibiting the myogenic constriction. Inhibition by RGD peptide could be explained by the fact that the vasodilatory effect of RGD peptides on {alpha}v{beta}3-integrin supersedes the vasoconstrictor effects of {alpha}5{beta}1-integrin ligation (31). The RGD peptide used in the present study, while being a ligand for both {alpha}5{beta}1- and {alpha}v{beta}3-integrins, preferentially affects {alpha}v{beta}3-integrin function (38). This peptide could therefore be inhibiting myogenic constriction via its vasodilatory effect through {alpha}v{beta}3-integrin and its competitive blockade of {alpha}5{beta}1-integrin. However, the observation that the selective blockade of {alpha}v{beta}3-integrin by anti-{beta}3-integrin antibody also inhibited myogenic constriction indicates that {alpha}v{beta}3-integrin by itself is necessary for this myogenic behavior. Although it should be noted that in isolated vascular smooth muscle cells antibody blockade of {alpha}v{beta}3-integrin causes a reduction in L-type calcium current (52), the fact that antibody blockade of {alpha}v{beta}3-integrin inhibited myogenic constriction without causing a significant initial vasodilation suggests that a complex interaction may exist between {alpha}v{beta}3- and {alpha}5{beta}1-integrins for regulating myogenic behavior. It is possible that, in the intact vessel, interactions between {alpha}5{beta}1- and {alpha}v{beta}3-integrins may exist such that both integrins participate in the development of myogenic constriction. Such interactions have been previously reported for these two integrins. For example, a cooperative interaction occurs in primary human foreskin fibroblasts as soluble fibronectin molecules bind {alpha}5{beta}1-integrin, causing fibronectin to be actively translocated along stress fibers and initiating fibronectin fibrillogenesis in a process that requires the cell to be anchored via {alpha}v{beta}3-integrins to focal adhesion contacts (37). Conversely, in human macrophages and erythroleukemia K562 cells that express {alpha}v{beta}3- and {alpha}5{beta}1-integrins, ligation of {alpha}v{beta}3-integrin inhibits {alpha}5{beta}1-integrin-mediated phagocytosis, indicating that ligand binding of {alpha}v{beta}3-integrin affects the function of {alpha}5{beta}1-integrin in a process of transdominant inhibition, also termed integrin cross talk (1, 2). Whether a similar kind of cooperative or inhibitory interaction between {alpha}5{beta}1- and {alpha}v{beta}3-integrins occurs during myogenic behavior requires further investigation.

In conclusion, evidence is provided that integrins are directly involved in myogenic constriction of isolated skeletal muscle resistance arterioles. Because myogenic constriction has important hemodynamic implications, a clear understanding of all the processes and molecules involved in its development could provide the basis for creation of new tools to manipulate vascular peripheral resistance and local blood flow, as well as therapies for alleviating vascular disorders such as those encountered in hypertension, diabetes, and aging.


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 ABSTRACT
 MATERIALS AND METHODS
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This research was supported by National Heart, Lung, and Blood Institute Grants HL-58690 and HL-62863 to G. A. Meininger and Grant 0225084Y from the American Heart Association, Texas Affiliate to L. A. Martinez-Lemus.


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. A. Meininger, Cardiovascular Research Inst., Dept. of Medical Physiology, Texas A&M Univ. Health Science Center, 336 Reynolds Medical Bldg., College Station, TX 77843-1114 (E-mail: 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.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
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