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Restoration of coronary collateral growth in the Zucker obese rat:

Impact of VEGF and ecSOD

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Abstract

The metabolic syndrome (MS), a condition characterized by several risk factors for coronary artery disease, including obesity, is associated with endothelial dysfunction and oxidative stress. Because proper endothelial function is essential for signaling of certain growth factors (vascular endothelial growth factor, VEGF) we hypothesized that coronary collateral growth (CCG) is impaired in a model of the MS. To test this hypothesis, we stimulated coronary collateral growth in pre-diabetic Zucker obese fatty rats (OZR) and lean littermates (LZR) by using episodic, repetitive ischemia (RI: 40 s left anterior descending arterial occlusion, 24/d for 14 d). Myocardial blood flow (MBF, radioactive microspheres) was measured in the normal (NZ) and collateral-dependent (ischemic) zones (CZ); CCG was assessed as a ratio of CZ/NZ flow (unity represents complete restoration of CZ flow). In LZR, CZ/NZ ratio increased from 0.18 ± 0.03 to 0.81 ± 0.07 after RI (P < 0.05). In contrast, in OZR rats CZ/NZ did not increase after RI (0.15 ± 0.04 vs 0.18 ± 0.04). To rectify abrogated collateral growth in OZR, we employed VEGF gene therapy (VEGF-transduced, strained-matched, cultured vascular smooth muscle cells [cVSMCs], delivered intracoronary). VEGF therapy modestly but not significantly increased the CZ/NZ ratio after RI (0.16 ± 0.05 vs 0.33 ± 0.06). To facilitate VEGF signaling,we reduced oxidative stress by transducing cVSMCs with both ecSOD and VEGF. This increased the CZ/NZ flow ratio after RI to 0.52 ± 0.04 (p < 0.05 vs. OZR [(0.19 ± 0.04]) indicating partial restoration of collateral growth. Our results demonstrate that coronary collateral growth is impaired in a model of the metabolic syndrome and that growth factor gene therapy with VEGF is made far more effective when it is coupled to an intervention that reduces oxidative stress.

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Authors and Affiliations

  1. Dept. of Physiology, Louisiana State University Health Sciences Center, 1901 Perdido St., Medical Education Building, New Orleans (LA), 70112, USA

    N. Hattan, W. M. Chilian & P. Rocic PhD

  2. Dept. of Pharmacology Cardiovascular Center of Excellence, Program in Gene Therapy Louisiana State University Health Sciences Center, New Orleans (LA), USA

    F. Park

Authors
  1. N. Hattan
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  2. W. M. Chilian
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  3. F. Park
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  4. P. Rocic PhD
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Corresponding author

Correspondence to P. Rocic PhD.

Additional information

Supported by NIH grants HL32788 (WMC), HL65203 (WMC), HL73755 (WMC), and COBRE RR018766 (FP, PR,WMC), and American Heart Association Scientist Development Grant (PR), AHA Postdoctoral Fellowship Award (NH, PR).

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Hattan, N., Chilian, W.M., Park, F. et al. Restoration of coronary collateral growth in the Zucker obese rat:. Basic Res Cardiol 102, 217–223 (2007). https://doi.org/10.1007/s00395-007-0646-3

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  • DOI: https://doi.org/10.1007/s00395-007-0646-3

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