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J Appl Physiol 98: 329-333, 2005. First published September 3, 2004; doi:10.1152/japplphysiol.00514.2004
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ACL deficiency impairs the vasoconstrictive efficacy of neuropeptide Y and phenylephrine in articular tissues: a laser speckle perfusion imaging study

Daniel Miller, Kevin Forrester, Catherine Leonard, Paul Salo, and Robert C. Bray

McCaig Centre for Joint Injury and Arthritis Research, Department of Surgery, University of Calgary, Calgary, Alberta, Canada

Submitted 4 May 2004 ; accepted in final form 31 August 2004


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Sympathetic-derived neuropeptide Y (NPY) helps regulate inflammatory responses in injury and disease, is a vasoconstrictor, and stimulates angiogenesis. Rupture of the anterior cruciate ligament (ACL) is a common clinical presentation that results in tissue inflammation, hyperemia, and angiogenesis in the intact medial collateral ligament (MCL). This study is the first to examine the vasoregulatory role of NPY in ACL-deficient knee joints by using the newly developed technique of laser speckle perfusion imaging (LSPI). MCL blood flow was measured in two groups of adult rabbits: unoperated control (n = 6), and 6-wk ACL transected (n = 5). Under anesthesia, the MCL was surgically exposed and tissue blood flow was imaged at high resolution using LSPI. NPY was applied to the MCL vasculature in topical boluses of 100 µl (dose range 10–14 to 10–9 mol), and the {alpha}-adrenoceptor agonist phenylephrine was applied in doses of 10–14, 10–10, and 10–7 mol. In control rabbits, topical administration of NPY or phenylephrine produced dose-dependent vasopressor responses (maximal effect at 10–9 mol NPY and 10–7 mol phenylephrine). In ACL-transected knees, there was little or no vasoconstrictive response to NPY at any dose. The response to phenylephrine was significantly reduced compared with control ligaments. Possible causes of the reduced vasoconstrictive response to NPY in the MCL after 6 wk of ACL deficiency include development of tolerance to the peptide due to a prolonged increase in sympathetic nerve activity or change in the distribution or functionality of the NPY Y1 receptors. Chronic ACL deficiency leads to profound and protracted hyperemia in associated articular tissues. Abrogation of a vasoconstrictor response to both NPY and phenylephrine in the MCL indicates that ACL deficiency induces major changes in the vascular physiological homeostasis.

blood flow; medial collateral ligament; anterior cruciate ligament; osteoarthritis

NEUROPEPTIDE Y (NPY) is a 36-amino acid peptide with a wide range of functions mediated by multiple receptor subtypes. It has recently been proposed that NPY may be an integrating factor between sympathetic nerves, blood vessels, and inflammatory responses to injury, stress, or disease (22). Located in large vesicles in sympathetic nerve terminals, NPY is secreted in conjunction with norepinephrine and potentiates and prolongs its effects (4, 20). NPY is itself a potent vasoconstrictor, contributing to peripheral vasomotor control via the NPY Y1 receptor subtype (3, 7). It is also a mitogen for vascular smooth muscle cells (17) and stimulates migration, proliferation, and capillary formation of human vascular endothelial cells in culture (23).

A recent body of evidence also suggests that NPY functions in the initiation and regulation of inflammatory responses such as those occurring after injury and in some disease states. NPY induces macrophages to secrete histamine, substantially increasing peripheral vascular permeability (9), and it induces secretion of TNF-{alpha} and IL-1{beta} from mast cells (11). On the basis of the above evidence, it seems that NPY is intimately connected with the regulation of blood flow, angiogenesis, and inflammation that occurs after injury.

One focus of our research is the physiological interaction occurring in diarthrodial joints in injury and disease states. In the knee, rupture of the anterior cruciate ligament (ACL) is a common clinical occurrence that induces inflammation, hyperemia, and angiogenesis in other articular tissues, such as the medial collateral ligament (MCL) (1, 10). These changes often culminate in the development of osteoarthritis within a few years (8, 21). We have used the ACL-deficient rabbit knee as a model to show that chronic joint instability induces increased blood flow, angiogenesis, and degraded mechanical properties of the intact MCL (1, 2). In addition, we have shown that there is a neurogenic component to this hyperemia involving another neuropeptide, calcitonin gene-related peptide (CGRP) (6). NPY can also be immunolocalized to the MCL and may be involved in many aspects of the tissue response to joint instability and incipient osteoarthritis (18, 19).

As an initial investigation in assessing the role of NPY in chronic joint instability, we chose to examine its vasoconstrictive activity in the uninjured rabbit MCL of ACL-deficient knees. Our hypothesis for the present study was that MCLs subjected to repeated microinjury through loss of joint stability would show a different vasoconstrictive activity profile than control tissues. Our laboratory has previously used the techniques of topical drug application and laser-Doppler perfusion imaging (LDI) to investigate the role of CGRP in joint hyperemia secondary to ACL rupture and to compare the activities of sympathomimetic drugs (15, 16). In the present study, we introduce the use of a novel imaging technique for the real-time assessment of joint tissue blood flow: laser speckle perfusion imaging (LSPI). Our laboratory has recently developed this technique to provide much more rapid and high-resolution perfusion images than LDI and published a rigorous comparison of the LSPI instrumentation and technique to the established LDI method (5, 6). The LSPI technique uses a charge-coupled device camera and custom software to image the speckle pattern produced when laser light interacts with living tissue. Changes in the speckle pattern produced by the movement of red blood cells are quantified in real time to give a numerical perfusion index that is linearly related to blood flow. In the present study, we used LSPI to measure dose-dependent vasoconstriction produced by the {alpha}1-adrenoceptor agonist phenylephrine, as well as by NPY. Comparison of the phenylephrine dose-response curve with that measured by LDI (15) allows further assessment of the two blood flow measurement techniques.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Eleven skeletally mature 1-yr-old New Zealand White rabbits (4.5–6 kg) were used in two cohort groups: unoperated control (n = 6) and 6-wk ACL transected (n = 5). Our laboratory's previous studies have shown no significant effect of sham operation on tissue blood flow at 6 wk (1, 2); therefore, a sham-operated group was omitted, and normal controls were used. Rabbits were kept on a 12:12-h light-dark cycle and fed standard laboratory chow and tap water ad libitum. All animals were treated and maintained according to the Canadian Council on Animal Care Guidelines.

ACL Transection

Rabbits were given 0.18 ml of acepromazine maleate (Atravet) intravenously and anesthetized with halothane (2–5%, 1.0 l/min O2). An anterior tibial draw test was performed to ensure that no prior ACL injury condition existed. An anterolateral surgical approach was used. The patellar fat pad was retracted, the ACL was isolated using a hooked probe, and the ligament was cut using a no. 11 surgical blade. A second anterior tibial draw was performed to ensure that the transection was complete. After surgery, rabbits were treated with standard antibiotics and allowed to resume normal cage activity for 6 wk.

Blood Flow Imaging

Under anesthesia, the MCL was surgically exposed. Overlying fascia was carefully dissected away without damaging the network of blood vessels supplying the MCL. Blood flow was measured using our recently developed LSPI. Full details of the instrumentation can be found in previous publications (5, 6). Briefly, a 635-nm laser source is connected by a fiber-optic cable to the LSPI instrument head, which also contains a black and white charge-coupled device camera with a close-focus imaging zoom lens. The instrument head was placed 23 cm directly above the MCL for a uniform and simultaneous illumination of the entire region of interest, and the lens focus was adjusted until the region of interest filled the camera field of view. Exposure time was set at 15 ms. LSPI camera output was fed directly to a live monitor for continuous video of the laser-illuminated tissue and to a computer for simultaneous capture and digitization of speckle images. High-resolution digital images were processed using custom LSPI algorithms to produce quantitative color-coded perfusion maps of tissue blood flow. Image pixels were analyzed to produce average perfusion values within a user-specified region defined by the anatomic borders of the MCL. Figure 1 shows examples of color-coded perfusion images of the MCL and the defined analysis regions used to produce the perfusion values.



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  		Fig. 1. Laser speckle perfusion images of rabbit medial collateral ligament in a control animal (A and B) and an experimental animal 6 wk after transection of the anterior cruciate ligament (C and D). Anatomic borders of the medial collateral ligament are indicated by ovals. A and B: vasoconstrictive effect of topically applied neuropeptide Y (NPY) in control animals (A: saline application; B: 10–12 mol NPY). C and D: no NPY-induced vasoconstriction in an anterior cruciate ligament-deficient joint (C: saline; D: 10–12 mol NPY).

 
Drug Application

After surgical exposure of the MCL, 100-µl aliquots of saline, phenylephrine, or NPY were applied topically to the MCL vasculature. Doses of NPY ranged from 10–14 to 10–9 mol. Doses of phenylephrine were 10–14, 10–10, and 10–7 mol. Perfusion images were captured every 10 s for 12 min after each drug application. The tissue was allowed to "rest" for 10 min between applications, during which time the joint was repeatedly washed with physiological saline (37°C, 0.9% NaCl).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
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Perfusion Imaging

LSPI gives rapid, high-resolution pictures of MCL blood flow in which individual blood vessels can be observed for the first time (an example is given in Fig. 1A). LSPI generates a real time "video" of tissue blood flow with a frame capture rate of 15 ms. Numerical perfusion indexes in perfusion units (PU) are continually updated for user-specified regions of interest selected within the image. Because capillary microcirculation in ligaments is relatively low, larger blood vessels supplying the MCL appear as yellow-green on a blue background in the color-coded image. In control MCLs, mean tissue perfusion was 7.29 ± 1.75 PU (n = 6).

Chronic joint instability produced by surgical transection of the ACL induced a statistically significant threefold increase in blood flow to the intact MCL. Mean MCL perfusion in ACL-deficient knees was 21.5 ± 1.20 PU compared with 7.29 ± 1.75 PU in control animals (P = 0.0002, Student's t-test). This is in agreement with previously published results using the ACL-deficient rabbit model, where MCL blood flow was determined by invasive infusion of the vasculature with colored microspheres to demonstrate a similar threefold increase in blood flow after 6 wk of ACL deficiency (2). The colored-microsphere technique generates absolute blood flow values in units of milliliters per minute per gram of tissue.

Figure 1C is an example of a perfusion map from the MCL of a 6-wk ACL-deficient knee. It is apparent from this image that the increased ligament perfusion is due to a greater number and density of blood vessels supplying the MCL. This also confirms our laboratory's earlier results showing angiogenesis occurring in the MCL of ACL-deficient knees (15).

Vasoconstrictive Drug Responses

Control knees.   Topical administration of NPY to the MCL in normal knees produced a dose-dependent vasoconstriction with maximal contraction occurring at the highest dose of 10–9 mol NPY. Mean perfusion value for control MCLs with saline application was 7.29 ± 1.75 PU; after the application of 10–9 mol NPY, this was reduced to a mean of 3.73 ± 1.12 PU (P = 0.03). Figure 1B shows an LSPI image of NPY-induced vasoconstriction compared with the same ligament after saline application (Fig. 1A); application of 10–12 mol NPY reduced MCL perfusion by 18% in this example.

ACL-deficient knees.   After 6 wk of ACL deficiency, the vasoconstrictive effects of NPY were significantly reduced. Mean MCL perfusion values after the application of 10–9 mol NPY were not significantly different from after saline application (19.26 ± 1.69 vs. 21.5 ± 1.20 PU). The bar graph in Fig. 2 shows the mean percent reduction in MCL perfusion produced by each dose of NPY in control and ACL-deficient knees.



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  		Fig. 2. Effects on perfusion with topical administration of NPY. Boluses of 0.100 ml were administered to the exposed medial rabbit knee joint. Values are shown as percent change ± SE. n Values are as for Fig. 3. *Significant difference between control and anterior cruciate ligament-deficient (ACL) knees for each dose of NPY, P ≤ 0.05 (Student's t-test).

 
Phenylephrine response.   To ensure that the LSPI technique gave similar responses to the established technique of LDI, we used the {alpha}1-adrenoceptor agonist phenylephrine at three doses (10–14, 10–10, and 10–7 mol). Figure 3 shows the mean percent drop in MCL perfusion after the application of phenylephrine to control and ACL-deficient joints. In control animals, the dose-response curve was very similar to a previously published curve, where MCL perfusion was measured using LDI (19). Phenylephrine produced a mean dose-dependent constrictor response in control MCLs that was significantly greater than the response in ACL-deficient joints (Fig. 3).



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  		Fig. 3. Vasoconstrictive effect of topically applied phenylephrine in rabbit medial collateral ligament measured by laser speckle perfusion imaging. Values are means ± SE; n = 6 for control animals, and n = 5 for anterior cruciate ligament-deficient (ACL-X) animals.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Loss of the ACL results in significant joint instability characterized by hyperemia, angiogenesis, inflammation, and degraded mechanical properties of articular tissues, including the MCL (1, 2, 14). There is also a relentless progression to osteoarthritis of the entire joint (8, 21). NPY has many diverse roles in neurotransmission, immune response, angiogenesis, and vasomotor regulation, and it has been proposed as a significant factor orchestrating all of these processes (22). Cleavage of NPY by dipeptidyl dipeptidase IV (CD26) produces the endogenous Y2 receptor ligand NPY-(3—36). This molecule has very low affinity for the Y1 receptor, which is predominantly responsible for the vasoconstrictive effects of NPY. The product NPY-(3—36) acts on the Y2 and Y5 receptors to stimulate angiogenesis. Thus processing of the NPY molecule can produce alternate responses and allow for the broad diversity of effects caused by NPY as allowed by the presence of multiple receptor subtypes.

NPY can be immunolocalized to the normal MCL, and there is evidence of considerable plasticity of peptidergic innervation in injured ligament (18). In the MCL of ACL-deficient knees, neurogenic hyperemia has been demonstrated (16). Joints with the saphenous nerve removed before ACL section did not exhibit the characteristic hyperemia of ACL-deficient joints with the saphenous nerve intact, and they more closely resembled control joints. Posttraumatic neurogenic inflammation may exacerbate joint instability by increased water content of articular tissues, altering the low-load biomechanical properties of supporting ligaments (16).

In the present study, we have shown reduced vasoconstrictive efficacy of NPY and phenylephrine in the MCLs of unstable, chronically inflamed knee joints. The vasoconstrictive effects of NPY are mediated by the Y1 receptor (3, 7), and the distribution and function of this receptor may be altered in the newly formed blood vessels of the MCL after ACL transection. The bioavailability of topically applied drugs may also be reduced as a consequence of dilution across the increased vascular volume and water content of the tissue.

Ongoing increased sympathetic nervous activity after injury may promote the development of tolerance to NPY: NPY coexists with norepinephrine in perivascular sympathetic nerves, and there is a complex interdependent cooperation between the two (20). Tolerance of the medial collateral vasculature to the {alpha}1-adrenoreceptor phenylephrine in the ACL-deficient model indicates increased sympathetic nervous activity, and NPY is secreted in larger amounts at high frequencies of sympathetic nerve stimulation (12). Increased tissue concentrations of NPY and norepinephrine will lead to downregulation of receptor expression. Loss of a sympathetic constrictor response eliminates one mechanism of moderating the hydrostatic pressure in the knee joint capillary beds, contributing to knee swelling, redistribution of tissue water content, and alteration of low-load viscoelastic behaviors.

NPY has several other roles in injury and immune reactions that likely contribute to the response of the MCL to joint instability. Our laboratory has previously shown a threefold increase in the microcirculatory volume of the MCL 6 wk after ACL transection, accompanied by increased water content of the tissue (14). NPY causes the secretion of histamine from mast cells (9), significantly increasing the permeability of vascular endothelium. This increased permeability, in conjunction with the return of normal hydrostatic pressure in the capillary vasculature after tolerance, may be a substantial contributor to the chronic edema in ACL-deficient joints. NPY also acts to promote angiogenesis via the NPY Y2 receptor (13), and our laboratory has previously shown increased vascularity associated with ligament injury that is correlated with ligament healing capacity (2).

This study also demonstrates the utility of LSPI for the study of vascular physiology. LSPI is a new technique that produces very rapid, high-resolution images of tissue blood flow and can be used to quantify vasomotor responses to injury, disease, pharmacological agents, or surgical intervention (5, 6). Figure 1A illustrates the detailed visualization of MCL blood vessels produced by LSPI. In our laboratory's previous studies of MCL blood flow, an older technique for blood flow measurement was used, LDI (15, 16). To provide a comparison between the two techniques for quantifying dose-dependent vasoconstriction, we used the {alpha}1-adrenoceptor agonist phenylephrine to induce constriction of MCL blood vessels and compared this with a similar curve measured using LDI (14). In each case, the highest dose of phenylephrine produced the greatest degree of vasoconstriction. A dose of 10–10 mol phenylephrine reduced blood flow in the MCL by 50 ± 4.8% as measured by LDI (Ref. 14, Fig. 1), and by 34 ± 6.3% in the present study using LSPI (Fig. 3). We conclude from this that LSPI gives comparable quantitative perfusion data to LDI, but allows for much more rapid imaging at a resolution high enough to visualize individual blood vessels in the MCL. LSPI can therefore be used to map both perfusion in blood vessels ranging in size from arteries to capillaries and their response to drug application.

Conclusion

Abrogation of the MCL vasoconstrictor response to NPY indicates that chronic ACL deficiency induces profound changes in the vascular physiology of articular tissues. Loss of the vasoconstrictive response to both NPY and phenylephrine suggests that there is increased sympathetic nervous activity in this injury model, leading to the development of tolerance to both sympathomimetic drugs and NPY. The actions of NPY on vasomotor regulation and permeability in joint injury and subsequent chronic inflammatory disease likely contribute to changes in tissue mechanical properties.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
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This work was supported by the Markin-Flannagan Undergraduate Student Research Program at the University of Calgary and by operating funds from the Canadian Institutes for Health Research. R. C. Bray is Senior Scholar of and P. Salo is a Scholar of the Alberta Heritage Foundation for Medical Research.


   ACKNOWLEDGMENTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Michael Doschak, Dr. Jason McDougall, and Craig Sutherland for expertise and advice.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. C. Bray, Dept. of Surgery, HMR 436, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1 (E-mail: rcbray{at}ucalgary.ca)

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.


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