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Ann Thorac Surg 2002;73:819-824
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in human internal mammary artery

^a Cardiovascular Research, Starr Academic Center, St. Vincent Heart Institute, Department of Surgery, Oregon Health Sciences University, Portland, Oregon, USA
^b Cardiovascular Research, Genentech, Inc, San Francisco, California, USA
^c Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China

Accepted for publication October 15, 2001.

* Address reprint requests to Dr He, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, P.R. China
e-mail: gwhe{at}cuhk.edu.hk

	Abstract

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Background. Vascular endothelial growth factor (VEGF) has been shown to have potential to treat ischemic diseases. Moreover, its vasorelaxing or vasodilatory effect might be favorable for relieving graft spasm. In this study, we examined the vasorelaxing effects of recombinant VEGF in isolated human internal mammary artery (IMA) and compared the responses to acetylcholine and nitroglycerin.

Methods. Isometric tension of IMA ring segments was measured with an organ bath technique. With an optimal resting tension determined from its individual length-tension curve, precontraction was induced by 10^-8 M U46619 and cumulative concentration-relaxation was measured by application of VEGF (10^-12 to 10^-8.5 M), acetylcholine (10^-10 to 10^-5 M), and then nitroglycerin (10^-4.5 M).

Results. Vascular endothelial growth factor induced concentration-dependent relaxation (EC₅₀: -9.89 ± 0.05 log M; E_max: 63.2% ± 7.3%) in IMA with intact endothelium. The relaxant responses to VEGF were significantly attenuated by pretreatment with N-nitro-L-arginine (L-NNA) alone and indomethacin + L-NNA, and totally abolished by removal of the endothelium or pretreatment with indomethacin + L-NNA + oxyhemoglobin. Internal mammary arteries became more sensitive to VEGF in the presence of indomethacin alone. However, acetylcholine-induced relaxation was not abolished by treatment with indomethacin + L-NNA + oxyhemoglobin (E_max: 16.9% ± 2.7%). The endothelium-independent relaxations induced by nitroglycerin were also significantly inhibited by administration of oxyhemoglobin.

Conclusions. The results demonstrate that VEGF-induced endothelium-dependent relaxation in the human IMA is mainly due to nitric oxide release. Although the vasorelaxing effect is not the primary advantage of this drug when it is used for angiogenesis, such effect may be advantageous in patients who also need a coronary artery bypass operation.

	Introduction

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Vascular endothelial growth factor (VEGF) is a mitogen for vascular endothelial cells derived from arteries, veins, and lymphatics, but it is devoid of consistent and appreciable mitogenic activity for other cell types [1]. VEGF is a fundamental regulator of normal and pathologic angiogenesis [2]. Recent animal studies have demonstrated the ability of VEGF to induce physiologically meaningful angiogenesis in the setting of myocardial or peripheral vascular ischemia [3]. Administration of VEGF has aided the development of collateral vessels and has improved blood flow and muscle function in animal models of limb ischemia [4]. Within the coronary system, intracoronary slow release or perivascular delivery of VEGF has been effective in promoting collateral development and improving myocardial blood flow in several animal models [5]. Similarly, adenoviral-mediated gene transfer has been shown to improve myocardial perfusion and function in the ischemic porcine heart [6]. Recent clinical studies have shown that local injection of naked plasmid DNA coding for VEGF leads to an improvement in myocardial ischemia [7], and gene therapy with VEGF results in a significant symptomatic improvement in patients with "inoperable" coronary artery disease [8].

In addition to its angiogenic effect, VEGF also exerts vasorelaxing or vasodilatory effects in vitro and in vivo, which have been shown to be endothelium dependent and nitric oxide (NO) related [9, 10]. Furthermore, it has been demonstrated that VEGF regulates endothelial NO synthase expression in cell culture [11], and improves vascular reactivity in vivo [12]. We have recently reported the vasorelaxing effect of VEGF in the aorta of the spontaneously hypertensive rats [13].

The internal mammary artery (IMA) is the most commonly used conduit artery for coronary artery bypass grafting (CABG). The excellent graft function of the IMA has been shown to be related to its physiologic properties, particularly to the endothelium-dependent relaxation [14]. However, despite its superior long-term patency, this small artery tends to spasm [15]. Therefore, during daily surgical practice, vasodilator agents such as papaverine, nitroglycerin, or calcium antagonists are used to prevent spasm of this arterial graft [16, 17].

When VEGF is used for angiogenesis in ischemic heart disease, some of the patients also require CABG. Whether VEGF has vasodilatory effect on the IMA is therefore important. However, the vascular responses of VEGF in human IMA have not been reported. We therefore designed the present study to examine the possible relaxant responses of VEGF in the human IMA. The vasoactive properties of VEGF were also compared with those of other endothelium-dependent and endothelium-independent vasodilators.

	Material and methods

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General
Human IMA from 22 patients aged 64.0 ± 9.0 years undergoing coronary artery bypass operation were studied without regard to sex and preoperative drug therapy. Approval to use discarded IMA tissue was given by the Institutional Review Board of St. Vincent Hospital. Discarded distal IMA segments proximal to the bifurcation were collected, stored in oxygenated physiologic solution (Krebs) maintained at 4°C, and delivered to the laboratory. The Krebs solution had the following composition (in mM): Na⁺ 144, K⁺ 5.9, Ca²⁺ 2.5, Mg²⁺ 1.2, Cl^- 128.7, HCO₃^- 25, SO₄^-2 1.2, H₂PO₄^- 1.2, and glucose 11. The solution was aerated with a gas mixture of 95% O₂ and 5% CO_2.

Organ bath technique
The IMA was placed in a glass dish with oxygenated Krebs solution and the surrounding connective tissue was dissected out. The vessel was then cut into 3-mm-long ring segments; four or six segments were taken from each patient. In some IMA ring segments, the endothelium was denuded by gently rubbing the intimal surface with a thin polyethylene tube. In the remaining segments, great care was taken not to touch the inner surface of the blood vessels. We found that this technique allowed the experiment to be carried out with functionally intact endothelium as determined, in this study, by the relaxation response to acetylcholine in the IMA ring segments with unrubbed endothelium.

Ninety-six IMA ring segments were investigated. Artery ring segments were mounted on two thin parallel stainless steel wire hooks in a 25-mL glass organ bath containing Krebs solution, maintained at 37°C, and continuously bubbled with 95% O₂ and 5% CO₂. The lower wire hook was attached to a micrometer-adjustable support leg and the upper to an isometric force transducer (model FT03, Grass Instruments, West Warwick, RI) to record changes in isometric forces, which were amplified and recorded on a polygraph chart recorder (Model 79, Grass Instruments, West Warwick, RI). After a 60-minute equilibration period, a normalization technique was applied to set the vascular ring segments at a pressure comparable to in vivo values. The details of this technique have been published previously [14, 16].

Briefly, each arterial segment was stretched up in progressive steps to determine the individual length-tension curve. A computer iterative fitting program (VESTAND 2.1, Yang-Hui He, Princeton University, NJ) was used to determine the exponential curve, the pressure, and the internal diameter. When the transmural pressure on each ring reached 100 mm Hg, determined from its own length-tension curve, the stretch-up procedure was stopped and the ring was released to 90% of its internal circumference at 100 mm Hg. This degree of the passive tension was then maintained throughout the experiment. After the normalization procedure, the IMA ring segments were equilibrated for at least 60 minutes.

Protocol
A cumulative concentration-response curve to thromboxane A₂ mimetic U46619 (10^-10 to 10^-6.5 M) was established. U46619-induced contractions were increased dose dependently. The results showed that U46619 at 10^-8 M induced 50% to 80% of maximal contractile responses in the human IMA ring segments.

The IMA ring segments from the same patient were allocated randomly into different groups. There were six groups (n = 8 in each group). One group had ring segments with denuded endothelium. In the other groups the IMA ring segments had intact endothelium and were incubated in the presence of indomethacin (7 µmol/L), N-nitro-L-arginine (L-NNA, 300 µmol/L), indomethacin (7 µmol/L) + L-NNA (300 µmol/L), indomethacin (7 µmol/L) + L-NNA (300 µmol/L) + oxyhemoglobin (20 µmol/L), or VEGF vehicle for 30 minutes before the precontraction was started.

All the ring segments were precontracted with U46619 at concentration of 10^-8 M. When the contraction reached a stable plateau (about 10 minutes), VEGF (10^-12 to 10^-8.5 M) or acetylcholine (10^-10 to 10^-5 M) was applied in cumulative concentrations at an interval between doses to allow the relaxation induced by the previous dose to reach a plateau. Then 300 µmol/L nitroglycerin was added to the organ bath if the previous relaxation was not complete. The relaxation was expressed as percent reversal of the U46619-induced precontraction.

Data analysis
The sensitivity of VEGF or acetylcholine was expressed as EC₅₀, the effective concentration causing 50% of maximal relaxation (E_max). The EC₅₀ was determined from each individual concentration-relaxation curve by a sigmoid logistic curve-fitting equation: E = MA^p/(A^p + K^p), where E is relaxant response, M is E_max, A is concentration, K is EC₅₀ concentration, and p is the slope parameter. A computerized program was used for the curve fitting and EC₅₀ values were determined and expressed as log₁₀ M (log M in Figures).

Statistical analysis was performed with SPSS software (SPSS, Inc, Chicago, IL). All values were expressed as mean ± SEM. Statistical comparisons of the percentage relaxation under different treatments were performed by two-way ANOVA (general linear model) with repeated measures, followed by post hoc Bonferroni test to detect the individual differences. E_max and EC₅₀ were compared by one-way ANOVA followed by post hoc Bonferroni test. p less than 0.05 was considered statistically significant; 95% confidence interval for difference (0.95 CI) was also shown when possible; n values refer to number of ring segments from separate patients.

Materials
Drugs used in this study and their sources were: L-NNA, indomethacin, hemoglobin, acetylcholine, nitroglycerin (Sigma Chemical Company, St. Louis, MO), and U46619 (Cayman Chemical, Ann Arbor, MI). Stock solutions of U46619 and acetylcholine were held frozen until required. VEGF was generously provided by Genentech (San Francisco, CA). All solutions were freshly prepared before daily use and protected from light.

	Results

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The internal diameter of the 96 IMA ring segments at an equivalent transmural pressure of 100 mm Hg (D₁₀₀) was 2.27 ± 0.04 mm as determined from the normalization procedure. When the IMA ring segments were set at a resting diameter of 90% x D₁₀₀, the equivalent transmural pressure (P₉₀) was 82.4 ± 0.5 mm Hg, and the resting force was 4.2 ± 0.1 g. U46619-induced precontraction force was 4.5 ± 0.2 g.

Removal of the endothelium nearly abolished the relaxant responses to VEGF (E_max: 8.4% ± 2.4% (Fig 1, Table 1). The VEGF-induced relaxations in IMA ring segments with intact endothelium were concentration dependent (EC₅₀: -9.89 ± 0.05 log M; E_max: 63.2% ± 7.3%). The magnitude of the relaxation induced by VEGF was unaffected by treatment with the cyclooxygenase inhibitor indomethacin (E_max: 74.2% ± 5.6%; p = 1.000 versus control E_max, and p = 0.2 versus control group). However, the sensitivity of VEGF was increased when IMA ring segments were incubated with indomethacin (EC₅₀: -10.90 ± 0.12 log M; p = 0.001 versus control; 0.95 CI: 0.64 to 1.36 log M). VEGF-induced relaxations were significantly attenuated by the treatment of either L-NNA alone or L-NNA + indomethacin, and were abolished by the treatment of L-NNA + indomethacin + oxyhemoglobin (p 0.01 versus control group; p = 1.0 versus endothelium-denuded group; Fig 1).

View larger version (26K): [in this window] [in a new window]   Fig 1. Mean concentration (-log M)-relaxation (percent reversal of U46619-induced precontraction) curves for vascular endothelial growth factor (VEGF) in isolated human internal mammary artery (IMA) ring segments with intact endothelium pretreated with indomethacin (Indo, 7 µmol/L), N-nitro-L-arginine (L-NNA, 300 µmol/L), indomethacin + L-NNA (I + L), indomethacin + L-NNA + oxyhemoglobin (I + L + Hb, 20 µm), or vehicle as control. Another group of IMA ring segments with endothelium-denuded (E-) was also tested. n = 8 in each group. Values are expressed as mean ± standard error of the mean. *p 0.01 versus control group (two-way ANOVA).

View larger version (30K): [in this window] [in a new window]   Fig 2. Mean concentration (-log M)-relaxation (percent reversal of U46619-induced precontraction) curves for acetylcholine in isolated human internal mammary artery (IMA) ring segments with intact endothelium pretreated with indomethacin (Indo, 7 µmol/L), N-nitro-L-arginine (L-NNA, 300 µmol/L), indomethacin + L-NNA (I + L), indomethacin + L-NNA + oxyhemoglobin (I + L + Hb, 20 µm), or vehicle as control. Another group of IMA ring segments with endothelium-denuded (E-) was also tested. n = 8 in each group. Values are expressed as mean ± standard error of the mean. *p 0.001 versus control group (two-way ANOVA).

View larger version (70K): [in this window] [in a new window]   Fig 3. Bar graphs depict nitroglycerin (300 µmol/L)-induced maximal relaxation in isolated human internal mammary artery (IMA) ring segments precontracted by U46619. The IMA ring segments with intact endothelium were pretreated with indomethacin (Indo, 7 µmol/L), N-nitro-L-arginine (L-NNA, 300 µmol/L), indomethacin + L-NNA (I + L), indomethacin + L-NNA + oxyhemoglobin (I + L + Hb, 20 µm), or vehicle as control. Another group of IMA ring segments with endothelium-denuded (E-) was also tested. n = 8 in each group. Values are expressed as mean ± standard error of the mean. *p = 0.001 versus other groups (one-way ANOVA).

	Comment

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Vascular endothelial and smooth muscle cells interact with each other in regulating vascular tone and in vascular growth or remodeling through various vasoactive substances, growth factors, and cytokines [8]. Vascular endothelial growth factor is produced in several cell types, such as smooth muscle cells and macrophages, as well as transformed cells, and VEGF production is stimulated by a variety of factors including growth factors, cytokines, and hypoxia [18]. Immunohistochemical studies have demonstrated that VEGF expression is localized predominantly to smooth muscle cells [19] in normal human vessels including aorta and IMA, as well as in the atherosclerotic segments of human coronary arteries. This finding suggests that VEGF may play a role in the maintenance and repair of vascular endothelium other than promoting angiogenesis. It has been shown that VEGF injected into the bloodstream or locally promotes reendothelialization in balloon-injured rat carotid arteries [20, 21]. Furthermore, extravascular VEGF gene transfer attenuates intimal growth and could be useful for the prevention of intimal thickening during vascular surgery [22]. Together, these data suggest that VEGF may be helpful in endothelial protection or enhancement of endothelial repair.

Growing evidence suggests that VEGF may be useful for treatment of ischemic heart disease due to therapeutic angiogenesis. Endothelial function is accepted as a crucial factor in graft longevity [12]. Our study demonstrated that VEGF induces an endothelium-dependent relaxation of human IMA in a dose-dependent manner. This result suggests that when VEGF is used as an angiogenic factor in ischemic heart disease, its vasorelaxing effects may be advantageous in CABG as far as vasospasm is concerned.

The endothelium is thought to produce and release various vasoactive substances, including prostacyclin, NO, endothelium-derived hyperpolarizing factor (EDHF), and endothelium-derived contracting factor, which modulate the tone of the underlying vascular smooth muscle. Nitric oxide is the primary factor on large conductance arteries, whereas EDHF is considered to be a major determinant of vascular caliber in small arteries and regulates the vascular resistance [22–24]. In a recent study [25] we found that EDHF is involved in the endothelium-dependent relaxation in the human IMA. In the present study, VEGF-induced endothelium-dependent relaxation in the presence of indomethacin plus L-NNA was significantly, but not completely, attenuated and the residual relaxation was abolished by addition of the NO scavenger oxyhemoglobin. This is consistent with our findings by direct measurement of NO in the porcine coronary artery [23] and the human IMA [25]. In contrast to the VEGF-induced relaxation, in response to acetylcholine in the presence of indomethacin and L-NNA plus oxyhemoglobin, the residual relaxation suggests the existence of EDHF in the human IMA and this finding is in accordance with those from our electrophysiological study [25, 26].

Further, although nitroglycerin elicited nearly complete relaxation to all the IMA ring segments even at the presence of L-NNA plus indomethacin, oxyhemoglobin markedly attenuated this endothelium-independent relaxation (Fig 3). Oxyhemoglobin can scavenge both endothelium-derived NO and NO from a NO donor. This finding agrees with a study by Zhou and Torphy [27], demonstrating that hemoglobin inhibited nitroglycerin-induced relaxation and cGMP accumulation in canine trachealis.

It has been shown, however, that systemic or intracoronary administration of VEGF results in a significant depressor response in various species of animals, a response that has been attributed to the profound vasodilation [10, 28]. This vasorelaxing effect is beneficial in CABG but its hypotensive effect should not be ignored.

In conclusion, VEGF-induced endothelium-dependent relaxation in the human IMA is mainly due to NO release. Although the vasorelaxing effect is not the primary advantage of this drug when it is used for angiogenesis, such effect may be advantageous in patients who also need coronary artery bypass operation.

	Acknowledgments

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This study was mainly supported by Providence St. Vincent Medical Foundation, Portland, OR, and Hong Kong Research Grants Council grant (CUHK7246/99M and CUHK4127/01M).

The technical assistance of the surgeon group and Kay Metsger and other nurses in Cardiac Operating Room, St. Vincent Hospital is also gratefully acknowledged. Doctor Liu is a Starr-He International Postdoctoral Fellow. Doctor Gary Grunkemier’s advice in statistical analysis for this study is gratefully acknowledged.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) 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): Anthony P.C. Yim Guo-Wei He Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, M.-H. Articles by He, G.-W. Search for Related Content PubMed PubMed Citation Articles by Liu, M.-H. Articles by He, G.-W. Related Collections Related Article