Fig. 2.

Microvessel wall barrier dysfunction in HFpEF. The metabolic syndrome induces via chronic systemic low-grade inflammation deleterious effects in coronary endothelial cells (EC). It leads to the degradation of the endothelial glycocalyx layer, thereby promoting endothelial immune cell adhesion and transmigration. Furthermore, metabolic syndrome-induced cellular oxidative stress may lead to glycocalyx damage and cell death of both endothelial and mural cells. In addition, pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, together with oxidative stress, increase vascular growth factor (VEGF)-A levels. Increased VEGF-A signalling weakens vascular barriers (e.g. loss of cell–cell junctions), which facilitates paracellular passage of immune cells and trans-vascular transport by transcellular vesiculo-vascular organ (VVO) formation. VEGF-A also stimulates vascular basement membrane remodelling through extracellular matrix (ECM) proteases activation, leading to reduced vascular stability and vascular regression