Complementary therapeutic effects of dual delivery of insulin‐like growth factor‐1 and vascular endothelial growth factor by gelatin microspheres in experimental heart failure

Abstract

Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure. Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt-mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS. IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable gelatin microspheres provide sustained and controlled growth factor release locally, exposing myocardial tissue without the side effects of systemic administration.