Differential effects of leptin and adiponectin in endothelial angiogenesis

Abstract

Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and endothelial adhesion molecules. The opposing actions of the two forms of adiponectin in endothelial cells have been recently demonstrated. Additionally, a local and systemic change to multimeric forms of adiponectin has gained importance. Thus detailed investigations on the potential interplay between these adipokines would likely result in better understanding of the missing links connecting CVD, adipokines, and obesity.

Figure 1

Structure of adiponectin receptors—AdipoR1 and AdipoR2 (66.7% amino acid homology).

Figure 2

Structure of leptin receptor isoforms—6 different isoforms of the leptin receptor Ob-R (a–f). Extracellular ligand-bind domains of receptor isoforms are identical but they differ at the C-terminus.

Figure 3

Differential effects of leptin and adiponectin in vascular endothelium. Dual effects of gAD and fAD on endothelium with and without inflammatory stimuli. Circulating fAD gets cleaved by leucocyte elastase (secreted from neutrophils) releasing globular domain (gAD) fraction. AdipoR1 and AdipoR2 receptors following engagement with fAD, signals downstream activating the following pathways (a) AMPK, (b) cAMP-PKA, (c) MAPK, and (d) PI3K-Akt. Activation of cAMP-PKA/AMPK causes increased NO production, decreased ROS generation, suppression of NF-κβ pathway leading to reduction in IL-18, and endothelial adhesion molecule expression. These events collectively lead to a decrease in EC permeability, motility, and migration. Activation of AMPK/PI-3k/Akt signalling pathway specifically leads to eNOS phosphorylation and NO release. In vitro studies have shown that gAD independently activates NF-κβ via AdipoR1/AMPK-Akt pathway. Proangiogenic/inflammatory effects of gAD have been shown to involve AMPK-Akt pathways. However, these pathways (AMPK-Akt) also contribute to an opposite effect of gAD in coexisting states of hyperglycaemia and inflammation. In hyperglycaemic and hyperinsulinaemic states, gAD improves endothelial dysfunction via activation of Akt-AMP-eNOS pathways and suppression of endothelial ROS generation via inhibition of NF-κβ signalling. The binding of leptin to its receptor (OB-Rb) leads to the phosphorylation of Ob-R/JAK2 complex. Subsequent activation of downstream signalling cascades including PI3k/Akt-STAT3 activation results in transcription of genes [MCP-1, TNF-α, IL-6/-2, and endothelin-1] involved in proatherogenic/angiogenic and inflammatory effects, potentiating endothelial proliferation. Additionally, leptin signalling in ECs also activates endothelial cell adhesion molecules, MMPs, and VEGF resulting in impaired endothelium-dependent vasodilatation promoting hypertension and atherosclerosis.