PlGF Repairs Myocardial Ischemia through Mechanisms of Angiogenesis, Cardioprotection and Recruitment of Myo-Angiogenic Competent Marrow Progenitors

Abstract

RationaleDespite preclinical success in regenerating and revascularizing the infarcted heart using angiogenic growth factors or bone marrow (BM) cells, recent clinical trials have revealed less benefit from these therapies than expected.ObjectiveWe explored the therapeutic potential of myocardial gene therapy of placental growth factor (PlGF), a VEGF-related angiogenic growth factor, with progenitor-mobilizing activity.Methods and ResultsMyocardial PlGF gene therapy improves cardiac performance after myocardial infarction, by inducing cardiac repair and reparative myoangiogenesis, via upregulation of paracrine anti-apoptotic and angiogenic factors. In addition, PlGF therapy stimulated Sca-1+/Lin− (SL) BM progenitor proliferation, enhanced their mobilization into peripheral blood, and promoted their recruitment into the peri-infarct borders. Moreover, PlGF enhanced endothelial progenitor colony formation of BM-derived SL cells, and induced a phenotypic switch of BM-SL cells, recruited in the infarct, to the endothelial, smooth muscle and cardiomyocyte lineage.ConclusionsSuch pleiotropic effects of PlGF on cardiac repair and regeneration offer novel opportunities in the treatment of ischemic heart disease.

Redefining Preeclampsia Using Placenta-Derived Biomarkers

“…113 Similarly, after myocardial injury, it can enhance repair via local angiogenesis, vasculogenesis, and cardiomyogenesis. 108 Circulating levels of PlGF in normal, nonpregnant individuals are low, if not undetectable with present assays. 114 However, increased circulating PlGF has emerged as a prognostic marker for clinical outcomes in nonpregnant patients with acute coronary syndromes.…”

“…108 It is highly expressed during pregnancy in the placenta, in particular by the syncytiotrophoblast. In nonpregnant individuals, low levels are normally produced by the heart, lung, thyroid, skeletal muscle, and adipose tissue.…”

Leukocyte driven-decidual angiogenesis in early pregnancy

“…It is not highly expressed in normal embryonic or adult tissues, but is elevated in many tumors and in ischemic heart repair. [135][136][137][138] In humans, PGF is encoded by two genes, PGF1 and 2. Both isoforms interact with the receptor FLT1 but not with KDR; only PGF2 binds neuropilin-1, 137 a coreceptor.…”

Mesenchymal Stem Cells: Roles and Relationships in Vascularization

“…52 These secreted factors include placental growth factor, which is a cytokine associated with the recruitment of EPCs. 53 Importantly, paracrine signaling between MSCs and EPCs is strongly dependent on the interplay between VEGF and BMP-2. BMP-2 plays an integral role in the osteogenic differentiation and function of MSCs.…”