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Ann Thorac Surg 1997;64:993-998
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Vascular Endothelial Growth Factor Attenuates Myocardial Ischemia-Reperfusion Injury

Division of Cardiothoracic Surgery, Department of Surgery, and Divisions of Cardiology and Biomedical Research, Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Hypoxic endothelial cell activation plays a key role in the myocardial dysfunction resulting from ischemia-reperfusion injury. Recent evidence suggests that vascular endothelial growth factor (VEGF) may, in addition to promoting angiogenesis, modulate various aspects of endothelial function and repair. We examined whether administration of VEGF in the cardioplegic solution might have a beneficial effect on myocardial ischemia-reperfusion injury in an isolated rat heart model.

Methods. Hearts from Sprague-Dawley rats were perfused with Krebs-Henseleit solution in a modified Langendorff apparatus. Percent recovery of cardiac output, coronary flow, stroke work, and percent increase in coronary vascular resistance were measured after 2 hours of global ischemia and 40 minutes of reperfusion. Coronary effluent was collected after ischemia and reperfusion for measurement of creatine kinase.

Results. Hearts receiving cardioplegia solution containing 125 µg VEGF showed significantly improved recovery of cardiac output, coronary flow, and stroke work, and significantly reduced coronary vascular resistance compared with hearts receiving hyperkalemic cardioplegia only (p < 0.05). Coadministration of a nitric oxide synthase inhibitor attenuated the VEGF-induced cardiprotective effects. Hearts treated with VEGF released significantly less creatine kinase compared with control hearts.

Conclusions. Addition of VEGF to hyperkalemic cardioplegia protects against myocardial ischemia-reperfusion injury in the isolated rat heart.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Acute myocardial ischemia followed by reperfusion results in a spectrum of derangements ranging from reversible dysfunction ("myocardial stunning") to irreversible necrosis [1]. Impairment of endothelial function, characterized among other things by a reduction in endothelium-dependent vasorelaxation, appears to play an important role in the process leading to myocardial injury in this setting [2]. By its nature a cardiac operation is often associated with a period of significant ischemia before or during the procedure and much of the mechanical dysfunction requiring inotropic support after cardiopulmonary bypass may be the result of reperfusion of this previously ischemic myocardium. Although the incidence of this complication has lessened with improvements in myocardial protective techniques, it remains a significant clinical problem, especially in patients who are acutely ischemic before surgery. Strategies designed specifically to protect the coronary endothelium, therefore, might provide an effective means to prevent subsequent myocardial reperfusion injury.

Vascular endothelial growth factor (VEGF), a 45-kd heparin-binding homodimeric glycoprotein, is a potent angiogenic mitogen acting exclusively on endothelial cells [3]. Widespread distribution of VEGF and its specific receptors flk-1 and flt-1 in the vasculature implies an important role for VEGF in maintenance of normal vascular function and development [4]. Ku and colleagues [5] and van der Zee and associates [6] demonstrated that VEGF stimulates nitric oxide release from vascular endothelial cells. Recent studies from our laboratory have demonstrated that VEGF induces neovascular formation in the ischemic hindlimb [7] and enhances reendothelialization [8] in addition to restoring endothelium-dependent vasomotor function after balloon-mediated arterial injury [9].

Based on these biologic properties, we reasoned that VEGF might be an appropriate agent to protect against myocardial reperfusion injury occurring as a result of endothelial damage. Accordingly, we examined whether administration of VEGF in the cardioplegic solution might have a beneficial effect on ischemia-reperfusion injury in an isolated rat heart model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animals
Hearts from male Sprague-Dawley rats (250 to 320 g weight) were studied in a modified Langendorff apparatus as described previously [10]. The experimental protocol was approved by the St. Elizabeth's Medical Center Institutional Animal Care and Use Committee and complied with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 86-23, revised 1985).

Perfusion of Isolated Hearts
Rats were anesthetized with intraperitoneal sodium pentobarbital (50 mg/kg) and heparinized (500 IU/kg intravenously). After thoracotomy, the hearts were rapidly excised and placed in saline at 4°C. The aorta was cannulated and perfused in a retrograde manner with Krebs-Henseleit bicarbonate buffer (in mmol/L: NaCl, 118; NaHCO₃, 25; KCl, 4.7; MgSO₄, 1.2; CaCl₂, 2.5; KH₂PO₄, 1.2; glucose, 11; pH 7.4) at a constant pressure of 70 cm H₂O. The perfusate was bubbled with gas mixture (95% O₂ + 5% CO₂) and equilibrated at 37°C. After an initial stabilization period, the hearts were converted to the working mode by filling the left atrium with oxygenated Krebs-Henseleit solution at a constant preload of 15 cm H₂O. The left ventricle ejected the perfusate through a pressure chamber into the aortic ejection line against a constant afterload of 70 cm H₂O. Aortic and coronary flow (CF) were measured by collecting the effluent from the aorta and the right ventricle respectively. Cardiac output (CO) was calculated as the sum of aortic and coronary flow. Aortic pressure was constantly monitored by a pressure transducer (Life Scope 8; Nihon Kohden Co, Japan) connected to the aortic cannula and was recorded on a strip chart recorder. Heart rate (HR) was calculated from the records of aortic pressure. Stroke work (SW) was calculated by the following formula:

Coronary vascular resistance (CVR) was calculated using the following formula:

where MAP is mean arterial pressure and RAP is right atrial pressure. Right atrial pressure was estimated to be equal to zero. After initial stabilization, a preservation protocol was designed to simulate clinical cardioplegic techniques used during standard cardiac surgical procedures.

Experimental Protocol
The experimental protocol is illustrated in Figure 1. After aortic cannulation, the hearts were perfused in the nonworking mode for 5 minutes and then converted to the working mode for 20 minutes. Baseline measurements were obtained at 10 and 20 minutes after starting the retrograde perfusion and were expressed as mean values. Unstable hearts showing a significant (>15%) drop in CO or in CF (>16 mL/min) during the baseline measurements were excluded from the study. Four experimental groups were studied with seven hearts in each group divided according to the composition of the cardioplegic solution (Table 1). Group I (control) received 4 mL hyperkalemic cardioplegia alone (5% glucose, HCO₃^-, 7 mEq/L; K⁺, 14 mEq/L; osmolarity, 330 mosm/L; pH 7.8); group II received cardioplegia with 50 µg VEGF (Genentech Inc) in 4 mL cardioplegia solution (12.5 µg/mL); group III received cardioplegia with the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME, 100 µmol/L); group IV received cardioplegia with L-NAME + VEGF. During 120 minutes of global ischemia at 25°C, additional cardioplegia with or without various agents as indicated above (6.25 µg/mL VEGF, L-NAME at same concentration) was infused at 30, 60, and 90 minutes. The dose of VEGF was based on preliminary experiments in which we found that this concentration was equally as effective as double the dose but superior to half of this amount. At the end of the 2-hour ischemic period, the hearts were reperfused with Krebs-Henseleit solution in the nonworking mode for 10 minutes and finally converted to the working mode for an additional 30 minutes. At 20 and 30 minutes of reperfusion, postischemic hemodynamics were measured and expressed as either percent recovery of the values before arrest (CO, CF, HR, SW) or percent increase in the case of CVR.

View larger version (17K): [in this window] [in a new window]   Fig 1. . The hearts were perfused in the nonworking mode for 5 minutes. Baseline measurements were obtained at 10 and 20 minutes after converting hearts to the working mode. Cardioplegic solution (see Table 1) was infused at 0, 30, 60, and 90 minutes of global ischemia. At the end of global ischemia, the hearts were reperfused in the nonworking mode for 10 minutes and in the working mode for an additional 30 minutes. Postischemic creatine kinase (CK) release was measured in the nonworking mode, and hemodynamics were measured at 20 and 30 minutes of reperfusion.

Measurement of Myocardial Water Content
Because VEGF (also referred to as vascular permeability factor) is known to affect vascular permeability, we measured the water content of the hearts at the end of the experimental protocol. Immediately after both the atria and great vessels were removed, the wet weight of the left and right ventricles was determined. The dry weight was obtained after desiccating the heart at 80°C overnight. Myocardial water content was calculated by the following equation:

Reagents
Reagents were purchased from Sigma Chemical (St. Louis, MO) unless otherwise specified. The 165-amino acid isoform of recombinant human VEGF was purified from transfected Chinese hamster ovary cells as previously described [12]. The purity of the material was assessed by a silver-stained sodium dodecyl sulfate–polyacrylamide gel electrophoresis gel and by the presence of a single NH₂-terminal amino acid sequence.

Statistical Analysis
All data were compared by one-way analysis of variance followed by Fisher's exact t test for further evaluation of differences between two means. All data are expressed as mean ± standard error of the mean. Probability value (p) less than 0.05 was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Cardiac Function
There were no significant differences in baseline hemodynamic measurements between any two of the four groups (Table 2). To elucidate any direct effect of VEGF on cardiac hemodynamics, we administered 50, 125, or 500 µg of VEGF under baseline nonischemic conditions for 60 minutes. However, these concentrations of VEGF produced no direct effects on HR, CF, CO, or mean arterial pressure during 60 minutes of observation after their administration.

View larger version (20K): [in this window] [in a new window]   Fig 2. . Percent recovery of (a) coronary flow (CF), (b) cardiac output (CO), and (c) stroke work (SW). Values are shown as mean ± standard error of the mean. (L-NAME = N-nitro-L-arginine methyl ester; VEGF = vascular endothelial growth factor; *p < 0.05 versus control.)

View larger version (19K): [in this window] [in a new window]   Fig 3. . Percent of coronary vascular resistance (CVR) after ischemia-reperfusion. Values are shown as mean ± standard error of the mean. (L-NAME = N-nitro-L-arginine methyl ester; VEGF = vascular endothelial growth factor; *p < 0.05 versus control.)

View larger version (19K): [in this window] [in a new window]   Fig 4. . Creatinine kinase (CK) release after ischemia-reperfusion. Values are presented as mean ± standard error of the mean; (L-NAME = N-nitro-L-arginine methyl ester; VEGF = vascular endothelial growth factor; *p < 0.05 versus control.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Vascular endothelial growth factor, also known as vascular permeability factor, has been shown to be an endothelial cell-specific mitogen in vitro [14] and an angiogenic growth factor in vivo [15]. We previously demonstrated that direct application of recombinant VEGF protein to the denuded surface of the rat carotid artery accelerates reendothelialization and reduces neointimal proliferation [8]. More recently, we showed that transfection of the gene encoding phVEGF₁₆₅ could not only accelerate reendothelialization of a balloon-injured rabbit femoral artery but also restore endothelium-dependent vasomotor reactivity as well [9]. Other studies have demonstrated that VEGF and its specific receptors, flk-1 (KDR) and flt-1, are expressed in embryonic vasculature [16] and that VEGF is produced in hypoxic myocytes in culture [17], chronically ischemic myocardium [18], and rat hearts after myocardial infarction [19]. The widespread expression and organ-specific distribution of VEGF messenger RNA and protein in normal rat tissues support the concept that VEGF may play a multifunctional role in the maintenance of vascular function in addition to mediating vascular growth [4]. Interestingly, Ku and coworkers [5] have demonstrated that VEGF stimulates the release of endothelium-derived relaxing factor (NO) in canine coronary arteries. Nitric oxide has been shown to function as an endogenous tissue-protective molecule during ischemia and reperfusion [20]. Based on these observations, we reasoned that VEGF may have the potential to protect against both the endothelial and myocardial injury associated with ischemia and reperfusion.

In the current study, we demonstrate that the inclusion of VEGF in cardioplegic solution resulted in significantly better functional recovery in isolated rat hearts subjected to 2 hours of global ischemia followed by 40 minutes of reperfusion. Vascular endothelial growth factor significantly improved cardiac hemodynamics as characterized by enhanced recovery of CO and left ventricular SW, and reduction of CVR compared with control hearts. This resulted in less myocardial cellular injury as measured by the CK content in the coronary effluent. These data clearly demonstrate that VEGF elicited a significant myocardial protective effect over crystalloid cardioplegia alone during global ischemia and reperfusion in this isolated rat heart model.

The mechanism of this effect is not likely to be a result of reduction of cardiac oxygen demand because VEGF failed to alter cardiac rate-pressure product (mean arterial pressure x HR) as compared with control hearts in our study (13,560 ± 490 versus 13,950 ± 450 mm Hg • beats/min, p = 0.56). The beneficial effect of VEGF was attenuated, however, by coadministration of the NO synthase inhibitor L-NAME (100 µmol/L). Vascular endothelial growth factor has been shown to stimulate NO release from endothelial cells in various sites, including the coronary arteries. It is likely that release of NO from the coronary vasculature after interaction between VEGF and its specific receptors accounts, at least in part, for the observed beneficial effects of this protein during ischemia and reperfusion. Furthermore, in the current study, rat hearts treated with L-NAME alone had very poor recovery (worse than control hearts), suggesting that endogenous NO production by functional endothelium may be a normal response to the insult resulting from ischemia and reperfusion.

There are several possible mechanisms whereby NO may elicit its beneficial effect in this setting. First, NO has been shown to scavenge oxygen-derived free radicals such as the superoxide anion. Restoration of flow to acutely ischemic endothelium results in the release of superoxide anions that can inactivate endogenous NO. A number of studies in animals and isolated hearts have shown that oxygen free radicals play a major causative role in myocardial reperfusion injury [21, 22]. Conversely, oxygen free radical scavengers such as catalase and superoxide dismutase have been shown to successfully inhibit cardiomyocyte injury associated with ischemia and reperfusion [23]. Therefore, enhanced NO production stimulated by VEGF may have inhibited the deleterious effects of these oxygen free radicals, thereby diminishing the extent of reperfusion injury.

In addition to the effects of oxygen free radicals, hyperkalemic crystalloid cardioplegia has been shown to impair endothelium-dependent relaxation of coronary vessels [23]. Reperfusion results in recovery of the response to contractile substances such as endothelin but not endothelium-dependent relaxation [24]. This imbalance produces increased CVR and decreased CF that may have been counteracted by VEGF-induced NO production, with resultant dilatation of the coronary vasculature.

As VEGF has been shown to increase tissue permeability [14], we were concerned that its inclusion in the cardioplegic solution might lead to increased myocardial edema. However, we could not find any difference in water content after treatment with VEGF compared with control hearts. Whether the use of an isolated heart model may have resulted in different effects of VEGF on tissue permeability from those observed in vivo remains to be determined.

The data obtained from the present study may be relevant to myocardial protective strategies in both conventional cardiac surgical procedures and cardiac transplantation. Cardioplegic solutions could be an ideal vehicle for the introduction of agents that target the perpetrators of endothelial injury associated with myocardial ischemia and subsequent reperfusion. Pinsky and colleagues [25] demonstrated that supplementation of NO donors in cardioplegia protected the myocardium in a heterotopic cardiac transplant model. Engelman and associates [26] administered the NO precursor L-arginine and observed improved myocardial function in isolated rat hearts. Rather than replacing lost endogenous NO with an exogenous NO donor, or by supplementation with an NO precursor, VEGF appears to stimulate NO release by preservation of normal or near normal endothelial function. In addition to its NO releasing capacity, VEGF is a powerful endothelial cell-specific mitogen that can accelerate reendothelialization and repair after injury. To the extent that coronary endothelium may be injured by hyperkalemic cardioplegic solutions in addition to the deleterious effects of hypoxemia and reperfusion, VEGF may confer the additional benefit of endothelial healing. Further investigation of the potential of this cardioprotective strategy is indicated.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported in part by a grant from Genentech Inc.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Symes, Cardiothoracic Surgery, St. Elizabeth's Medical Center, 11 Nevins St, Suite 306, Boston, MA 02135–2997.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James F. Symes Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luo, Z. Articles by Symes, J. F. Search for Related Content PubMed PubMed Citation Articles by Luo, Z. Articles by Symes, J. F.