Hyperlipidemia induced dysregulation of placenta growth factor expression

Patients with metabolic syndrome and diabetes are strongly predisposed to develop atherosclerotic cardiovascular disease (e.g., coronary and peripheral artery disease). Collateral artery growth (arteriogenesis), a physiological mechanism of vascular remodeling which might compensate for arterial occlusion, is depressed in diabetes. We thus investigated expression of a key arteriogenic factor, placenta growth factor (PlGF), in coronary arteries of miniature swine models of hyperlipidemia and diabetes/hyperlipidemia. Feeding of a high‐fat/cholesterol diet (46% kcal from fat, 2% cholesterol; N=18) reduced coronary artery PlGF mRNA expression to ~60% of control (N=15; p<0.01). PlGF expression was further reduced in pigs fed either a 75% kcal from fat diet (~15% of control; N=2) or fed the 46% fat diet after alloxan treatment to induce diabetes (~20% of control; N=2) (p<0.001 vs. control, both groups combined). Thus, the combination of diabetes (hyperglycemia) and hyperlipidemia did not dysregulate PlGF above hyperlipidemia alone. Elevated total cholesterol was strongly predictive for reduced PlGF expression (N=34, r 2 =0.2, p<0.01), whereas there was no correlation between PlGF and peak insulin (N=18) or peak glucose (N=21) during intravenous glucose tolerance test. Plasma triglycerides also were not predictive for reduced PlGF levels (N=21). Tissue PlGF protein levels were similar between groups (N=12), consistent with the fact that PlGF is a secreted protein. We hypothesize that hypercholesterolemia‐induced endothelial cell dysfunction leads to reduced serum PlGF levels and decreased arteriogenic potential in diabetes and metabolic syndrome. Support: NIH HL062552 , RR013223 (MS).