Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium

Abstract

Mazagova M, Buikema H, Landheer SW, Vavrinec P, van Buiten A, Henning RH, Deelman LE. Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium. Am J Physiol Heart Circ Physiol 304: H709 -H718, 2013. First published December 21, 2012 doi:10.1152/ajpheart.00543.2012.-Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endotheliumdependent mechanism involving altered caveolar endothelial NO synthase signaling. growth differentiation factor 15; aorta; endothelium; mice; caveolae; caveolin-1 GROWTH DIFFERENTIATION FACTOR 15 (GDF15), also called macrophage inhibitory cytokine (MIC)-1, is a distant member of the transforming growth factor (TGF)-␤ family and the result of posttranslational modification of the product of an early response gene (4). Upregulation of GDF15 has been demonstrated after chemical and hyperoxic injury of the lung, by surgical, chemical, and heat-induced injury of the liver (19), and after ischemia-reperfusion injury of the heart (15), indicating that GDF15 is a general mediator of the organ injury response. Furthermore, GDF15 is emerging as an independent predictor of cardiovascular disease (CVD) in the elderly and a predictor of prognosis in patients with established CVD (17,20,21). An association between GDF15 levels and endothelial dysfunction was found in an elderly population (21). Hence, endothelial dysfunction is considered the first step in the chain of events leading to atherosclerosis and CVD. It comprises an imbalanced production of vasodilating and vasoconstricting substances by th...

Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke

“…4 By comparing endothelial function in wild type and GDF-15 knocked out mice GDF-15 was recently demonstrated to directly modulate the endothelial-dependent NO synthase pathway in the aortas of mice. 31 Our observations are also in agreement with other lines of evidence suggesting a significant role of GDF-15 in vascular brain injury. For instance, higher GDF-15 levels have previously been reported to be strongly related to worse functional status in the acute phase of ischemic stroke in humans.…”

Expanded Haemodialysis Therapy of Chronic Haemodialysis Patients Prevents Calcification and Apoptosis of Vascular Smooth Muscle Cells in vitro

“…GDF-15 has been introduced as a biomarker for cardiovascular events and ­cardiovascular risk stratification [42-44] and several vascular diseases including STEMI [42], coronary artery disease [43, 45], stroke [46] as well as renal and cardiac damage in general [47-49]. In addition to its value as a surrogate parameter, an active role in atherosclerosis and other vascular pathologies has been suggested [50, 51]. Whether the lowered GDF-15 production in cells incubated with HRO serum is causally involved in vascular calcification is speculative, as its role in cardiovascular disease is still unclear and not sufficiently examined.…”

Growth differentiation factor 15 in adverse cardiac remodelling: from biomarker to causal player

“…118 Increased adhesion molecule expression, reduced anticoagulant properties, and imbalanced production of vasodilating and vasoconstriction substances all lead to endothelial dysfunction. 119 There are sufficient indications that GDF15 causes endothelial dysfunction by impairing vascular contraction and relaxation, which consequently could have a large impact on the function of the heart, by inducing not only large artery disease but also microvascular disease, which is associated with a deteriorating cardiac function. 120 Mechanistically, Mazagova et al 119 showed that the vascular contractility in response to vasoconstrictor agents was repressed under presence of GDF15, suggesting that GDF15 affects the NO system in endothelial cells.…”