Research ArticleCardiovascular Disease

Evidence for a protective role of placental growth factor in cardiovascular disease

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Science Translational Medicine  02 Dec 2020:
Vol. 12, Issue 572, eabc8587
DOI: 10.1126/scitranslmed.abc8587

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Protection through PlGF

Risk factors that promote vascular injury have been linked to atherosclerosis and cardiovascular events, but factors involved in vascular repair have received less attention. Chen et al. focused on placental growth factor (PlGF), which promotes endothelial cell growth and survival in response to ischemia. They identified links between high plasma PlGF and increased coronary artery disease and increased risk of acute cardiovascular events in a large cohort of individuals. PlGF was released from injured endothelial cells and regulated endothelial and smooth muscle cell repair. Stable atherosclerotic plaques exhibited higher PlGF expression, and a high ratio of circulating PlGF to the cell stress marker TRAIL receptor-2 indicated lower cardiovascular risk. Results help identify a protective mechanism for PlGF in cardiovascular disease.

Abstract

Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.

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