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Ann Thorac Surg 1999;68:825-829
© 1999 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Up-regulation of vascular endothelial growth factor mrna and angiogenesis after transmyocardial laser revascularization

^a Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois, USA

Address reprint requests to Dr Horvath, Division of Cardiothoracic Surgery, Northwestern University Medical School, Wesley 1030, 251 E Chicago Ave, Chicago, IL 60611
e-mail: khorvath{at}nmh.org

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Angiogenesis has been proposed as a potential mechanism whereby transmyocardial laser revascularization (TMLR) has provided clinical relief of angina. Experimental work has found histologic evidence supporting this, as well as an improved response when angiogenic growth factors have been added to TMLR. The purpose of this study was to demonstrate that the molecular response to TMLR was an increase in the production of endogenous vascular endothelial growth factor to promote angiogenesis.

Methods. Ameroid constrictors were placed on the proximal circumflex artery in 12 domestic pigs. After a chronic ischemic zone was established the animals were randomly divided into two groups. In the TMLR group the ischemic zone was treated with carbon dioxide laser. In the control group the ischemic zone was untreated. Six weeks later the animals were sacrificed, and sections from the ischemic zone and the nonischemic zone were submitted for immunohistochemical, histologic, and molecular analysis. Messenger RNA was obtained from northern blot analysis after being probed with vascular endothelial growth factor.

Results. There was a twofold increase in the vascular endothelial growth factor messenger RNA in the ischemic zone of the TMLR group compared with the control group. Additionally, there was a threefold increase in the number of new blood vessels in the ischemic zone of the TMLR group compared with the control group.

Conclusions. Transmyocardial laser revascularization promotes angiogenesis by upregulation of vascular endothelial growth factor. The resulting angiogenesis could be the principle mechanism for the clinical efficacy of TMLR.

	Introduction

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The use of a carbon dioxide (CO₂) laser to treat patients with end-stage coronary artery disease not amenable to conventional revascularization has yielded a significant reduction in angina symptoms [1–5]. The patient’s response to treatment is often immediate and improves progressively during the ensuing 6 to 12 months. As perfusion scans have improved during the same time, it has been suggested that angiogenesis is the potential mechanism by which transmyocardial laser revascularization (TMLR) achieves its effect.

Experimental studies have shown histologic evidence of angiogenesis as well as improved responses when angiogenic growth factors are used in conjunction with TMLR [6–12]. Additionally, we previously showed functional improvement that was most likely a result of angiogenesis after TMLR in a chronic ischemia model [13]. If angiogenesis is a mechanism of TMLR, then in addition to histologic evidence there should be evidence of increased production of growth factors at the cellular level. The purpose of this study was to show that the molecular response to TMLR was increased production of endogenous vascular endothelial growth factor (VEGF) to promote angiogenesis.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Animal model
Hughes and colleagues [12] performed a series of experiments in a standard model of chronic myocardial ischemia (ameroid occlusion of the circumflex artery). For those experiments the animals had three operative procedures during a 12-week period. In the first operation an ameroid occluder, which slowly constricts the circumflex artery, was placed. Six weeks later the animals were randomly divided into two groups. The TMLR group had transmyocardial revascularization by CO₂ laser to the ischemic zone, and the control group had a sham operation and received no treatment of the ischemic zone. At 12 weeks after the initial operation the animals had repeat thoracotomies to harvest tissue specimens and were sacrificed.

Animals received humane care as approved by the Center for Experimental Animal Research at Northwestern University and in compliance with the "Guide for the Care and Use of Laboratory Animals," published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).

Anesthesia
Twelve Yorkshire pigs of either sex weighing 15 to 20 kg were anesthetized with telazol (10 mg/kg), xylazine (0.25 mg/kg), and atropine (2 mg) intramuscularly, followed by sodium thiamylal (2.5%, 10 mg/kg) intravenously. After incubation, maintenance anesthesia was maintained with isoflurane (Abbott Laboratories, Chicago, IL). Before exposure of the heart, bretylium (10 mg/kg) was administered intravenously. The same anesthetic regimen was used for each of the three different surgical procedures.

Operative technique
At the initial operation, with sterile technique, the heart was exposed through a small left thoracotomy, and the pericardium was opened. The proximal left circumflex artery was dissected free and an ameroid constrictor (Research Instruments Mfg, Corvallis, OR) with an internal diameter of 2.5 mm was placed around the origin of the left circumflex artery. The pericardium and chest were then closed. The animal was allowed to recover. The animals were ambulatory before leaving the operating room suite and were monitored daily by a veterinarian and his staff, as well as the surgical team. Adequate food and water were provided and intake as well as weights were measured daily. Antibiotics were administered intramuscularly for 3 days postoperatively. Pain medications were also given intramuscularly until the animals were ambulating without difficulty and exhibiting normal activity levels. At the second operation, through a larger left thoracotomy, the pericardium was reopened and the heart reexposed. Blood pressure was monitored through an arterial catheter placed in the left internal mammary artery. Electrocardiographic monitoring was also used.

As previously described [13], dobutamine stress echocardiography was done to confirm the presence of chronic ischemia in the circumflex distribution and to rule out infarction. In this animal model, dobutamine stress echocardiography provided an assessment of the viablity of the myocardium and a method of determining the extent of ischemia. The dobutamine stress echocardiography protocol [13] mimics the dobutamine stress echocardiography that assesses ischemia clinically. The echocardiography was also used to confirm transmural penetration by the laser. The circumflex territory (ischemic zone) was then treated (n = 6) with transmyocardial revascularization by CO₂ laser (PLC Medical Systems, Franklin, MA). In control animals (n = 6), the same procedure was done, except the ischemic zone was not treated. Transmural channels (23 ± 2) were created in a distribution of one channel per square centimeter in each of the TMLR-treated animals. The thoracotomies were then closed and the animals allowed to recover. The aforementioned postoperative care was then reinstituted. At the time of sacrifice, 6 weeks later, the animals had repeat thoracotomy. Using sterile technique, transmural cubes of myocardium were excised from the circumflex territory as well as adjacent to the mid left anterior descending artery. These specimens were snap frozen in liquid nitrogen. The animals were exsanguinated and the hearts excised. Complete cross-sections were taken and fixed in 10% formalin.

Vascular endothelial growth factor mRNA analysis
Frozen myocardium was homogenized with a polytron in Trizol Reagent (Gibco Life Technologies, Gaithersburg, MD), which is a monophasic solution of phenol and guanidine isothiocyanate. The RNA was further purified with a phenol-chloroform extraction. The RNA pellet was precipitated in ethanol and dissolved in formamide. Its concentration was calculated from the absorbance reading at 260 nm. The purity was determined with the 260/280 nm absorbance ratio being 1.8 or greater. For northern blots, 10 to 20 µg of total RNA was fractionated by electrophoresis on a formaldehyde denaturing gel and transferred with Gibco BRL Blot Transfer Apparatus 11 x 14 cm onto a GeneScreen Plus Hybridization Transfer Membrane (Dupont, Wilmington, DE). The human VEGF, a 996-bp complementary DNA, and human 28S ribosomal RNA, a 700-bp complementary DNA, probes were labeled with [³²P] dATP (Amersham, Rochester, NY) using a random priming labeling kit (Prime-It II; Stratagene, Beltsville, MD) and purified of unincorporated nucleotides with Stratagene’s NucTrap Probe Purification Column. The specific probe activity used in the experiments was 2 x 10⁷ cpm. The blot was prehybridized at 42°C overnight and hybridized at 42°C overnight in hybridization solution (50% deionized formamide, 5x SSC, 50 mmol/L NaPO₄, pH 6.5, 0.1% sodium dodecyl sulfate, 5x Denhardt’s solution, and 500 µg/mL salmon sperm DNA). Nonspecifically bound probe was removed, with 2 or 3 manual washes in a hybridization roller bottle in wash solution (0.1x saline sodium citrate/0.1% sodium docecyl sulfate) for 5 minutes at room temperature and then twice for 30 minutes at 50° to 60°C in the hybridization chamber. The blot was allowed to dry and was wrapped in cling wrap. For quantitative analysis of expression, the blot was placed in a Fuji imaging plate for 1 to 2 hours and then scanned with a STORM Bioimager analyzer. The scanner is hooked up to a computer that uses a program called ImageQuantaNT (Molecular Dynamics, Sunnyvale, CA) to quantitate the highlighted bands. Autoradiography was also carried out with Hyperfilm (Amersham) at -80°C for 12 to 24 hours. The volume values of the 28S ribosomal RNA was used as a denominator for the VEGF messenger RNA (mRNA) values as a control to correct for the possible differences in RNA loading and transfer in northern blots.

Histologic analysis
After formalin fixation the sections were embedded in paraffin and stained with hematoxylin and eosin. The left anterior descending artery and the left anterior descending and circumflex territories were reviewed by two cardiac pathologists masked to treatment group. Factor VIII immunohistochemistry was performed, and blood vessels were then identified by positive factor VIII staining and counted at 200x magnification. Additional immunohistochemical staining for VEGF protein was done using a polyclonal antibody (sc-152; Santa Cruz Biotechnology, Santa Cruz, CA) in 1:25 antibody dilution.

Statistically, Student’s t test was done and differences were considered significant at a p value less than 0.05. The p values given are two-sided. Results are expressed as mean ± standard deviation.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
There were no significant hemodynamic or electrocardiographic differences between the animals at the second or third operations. We previously reported the functional results as based on echocardiography using this animal model [13]. Surveillance echocardiography on these animals showed the ischemic effect of the ameroid occluder at the second operation. For both the VEGF mRNA and histologic analyses, comparisons of the results were made between the laser-treated ischemic zones in the TMLR animals and the untreated ischemic zones in the control animals. To serve as an additional control, additional comparisons of the results were made between the ischemic zone and the nonischemic zone for each animal. Figure 1 is an image of the result of a northern blot comparing the prevalence of VEGF mRNA in the ischemic zone of laser treated animals (lanes 1 through 6) against that of the ischemic zone of untreated animals (lanes 10 through 15). This northern blot shows a higher level of radioactivity and therefore an increased amount of the corresponding VEGF mRNA in the laser-treated ischemic tissue. Quantitation of northern blots such as this is shown in Figure 2, which indicates an increase of more than twofold, in the amount of VEGF mRNA in the ischemic zone of the laser treated animals compared with the ischemic zone of the untreated control animals (p = 0.01). There is also a significant (p = 0.01) increase in the VEGF mRNA in the ischemic zone compared with the nonischemic zone of the laser-treated animals. There was no significant difference between the nonischemic zones in the treated and untreated control animals, or between the ischemic and nonischemic zones in the untreated control animals.

View larger version (21K): [in this window] [in a new window]   Fig 1. Northern blot analysis of vascular endothelial growth factor expression. Lanes 1 through 6 are from the ischemic zone of laser-treated animals. Lanes 10 through 15 are from the ischemic zone of untreated control animals. Lane 8 is from a human endothelial cell control. Lanes 7 and 9 are blank.

View larger version (34K): [in this window] [in a new window]   Fig 2. Vascular endothelial growth factor (VEGF) messenger RNA (mRNA) quantitation of northern blot data from transmyocardial laser revascularization (TMLR) and control animals. Left anterior descending artery (LAD) (nonischemic zone, solid bars) and Cx (ischemic zone, hatched bars) are compared for both groups of animals. The TMLR-treated ischemic zone shows increased VEGF mRNA compared with all other myocardium (*p = 0.01). No difference in VEGF mRNA between the TMR LAD, control Cx or control LAD (p = not significant).

View larger version (116K): [in this window] [in a new window]   Fig 3. Factor VIII immunohistochemical staining of myocardium. (A) Nonischemic zone from a laser-treated animal. (B) Ischemic zone from the same animal. There is a significant increase in the number of blood vessels in the laser-treated ischemic zone (original magnification, x100).

View larger version (33K): [in this window] [in a new window]   Fig 4. Number of blood vessels per 200x high-powered microscopic field in the nonischemic zone (LAD, solid bars) and the ischemic zone (Cx, slashed bars) from laser-treated and control animals. The laser-treated ischemic zone had a significantly higher number of blood vessels per high-powered field compared with all other sections of myocardium (*p = 0.01). There is no significant difference in the number of blood vessels per high-powered field between all other sections (p = not significant).

	Comment

Top Abstract Introduction Material and methods Results Comment References

Clinically, transmyocardial revascularization by CO₂ laser has been approved for use in the treatment of severe angina. Patients with angina have chronic myocardial ischemia; Therefore, to better understand the mechanism of TMLR it is important to use a model of chronic ischemia. A porcine model using an ameroid constrictor establishes an ischemic zone in the area subtended by the constrictor [14]. To account for the angiogenic response that this constrictor itself might induce, we used two types of controls. Each animal served as its own control by comparing the VEGF mRNA and histologic results from the nonischemic zone with those from the ischemic zone. Additionally, a group of animals that had the same coronary occlusion were not treated with the laser. The control animals did not have a significant increase in the amount of VEGF mRNA or an increase in the number of blood vessels per high-powered microscopic field.

New blood vessels in the laser channel remnant or as a result of a laser injury have been shown previously [6, 8–11]. Several of those experiments were done using a different laser and in nonischemic models. A comparison of these results to those of the present study is therefore limited; however, the vessels that were found were in the channel remnants and were often surrounded by scar and necrotic tissue, whereas vessels identified in the present study were at some distance from the laser channel, outside the channel remnant.

Other studies on the combined use of TMLR with angiogenic growth factors found enhanced responses both histologically and functionally [6, 7]. Although this synergy eventually may be the best way to achieve the ideal clinical result, it has not been shown previously that TMLR alone enhances the endogenous production of angiogenic growth factors. This production undoubtedly will decrease over time and the exogenous addition of angiogenic growth factors might be needed to continue this response.

Further experimentation must be done to determine the peak time of the angiogenic response after TMLR. Additionally, the increase in endogenous growth factor production after treatment with various types of lasers should be compared. In addition to comparing various wavelengths of light, the different approaches for TMLR require investigation as well. Percutaneous TMLR, which creates a small subendocardial injury, will not result in the same stimulation of angiogenesis and therefore might not yield the same symptomatic and functional improvement.

In summary, we found that transmyocardial revascularization by CO₂ laser stimulated angiogenesis in ischemic myocardium. Upregulation of one of the important angiogenic growth factors, VEGF, promoted an increase in the number of new blood vessels after TMLR. This resulting angiogenesis might be the principle mechanism for the clinical efficacy of TMLR.

	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): Keith A. Horvath David A. Fullerton Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Horvath, K. A. Articles by Fullerton, D. A. Search for Related Content PubMed PubMed Citation Articles by Horvath, K. A. Articles by Fullerton, D. A.