Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways

Abstract

Regulated endothelial exocytosis of Weibel-Palade bodies (WPBs), the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflammation, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells (ECs) through VEGF receptor 2 (VEGFR2) signaling pathways. Stretch triggers a rapid release (within minutes) of von Willebrand factor and interleukin-8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane. We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCγ1/calcium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic targets in limiting hypertensive stretch-related inflammation.

von Willebrand Factor as a Biological Sensor of Blood Flow to Monitor Percutaneous Aortic Valve Interventions

“…25 In our study, the observations of a sudden rise in VWFpp in situations where an increase of arterial luminal pressure is observed (such as TAVI or HeartMate-II LVAD patients), and the lack of VWFpp increase in a model without endothelium, is consistent with this hypothesis.…”

The “double whammy” of a continuous-flow left ventricular assist device on von Willebrand factor

“…Both endothelial cells and platelets secrete vWF, with in vitro studies revealing that vWF production in endothelial cells is regulated by a mechano-transduction pathway that shares components that both activate and upregulate NO. 9 NO is the primary dilatory signal for the peripheral vascular function tests, known to be reduced in CF-LVAD recipients compared with age-matched healthy controls and patients with heart failure. 8 Both vWF and NO share a common intercellular receptor (vascular endothelial growth factor receptor 2), which increases NO through the activation of Akt and the secretion of vWF into the plasma by the exocytosis of Weibel-Palade bodies through phosphoinositide-specific phospholipase g1 and the calcium pathway.…”

“…8 Both vWF and NO share a common intercellular receptor (vascular endothelial growth factor receptor 2), which increases NO through the activation of Akt and the secretion of vWF into the plasma by the exocytosis of Weibel-Palade bodies through phosphoinositide-specific phospholipase g1 and the calcium pathway. 9 Pulsatility stimulates vWF production, whereas NO release seems to result in a negative feedback loop, inhibiting the exocytosis of vWF by endothelial cells (Figure 1, A). Thus, the interwoven nature of NO and vWF has somewhat complicated repercussions in circulatory systems with reduced pulsatility.…”

“…[1][2][3][4]8 Specifically, in vitro studies have documented a shared mechano-transduction pathway in endothelial cells for the secretion of clotting factors and the production of the vasodilator nitric oxide (NO), a key vasodilator that has been recognized to be attenuated in CF-LVAD recipients. [9][10][11] Vincent and colleagues 1 recently revealed a dose-response relationship between reduced pulsatility and attenuated plasma clotting factors in swine implanted with a CF-LVAD. We will briefly review these findings and provide commentary on how CF-LVADs that, by attenuating arterial pulsatility and generating high pump-shear stresses, disrupt clotting factors and appear to result in a ''double whammy'' for vWF and ultimately nonsurgical bleeding.…”

Endothelial mechanosensors: the gatekeepers of vascular homeostasis and adaptation under mechanical stress

“…These responses serve to maintain vascular homeostasis through locally changing hemodynamics and prevent vascular cells from damage by mechanical injury [65,85,99]. Mechanical stress-induced sustained responses are relatively slow, adaptive and eventually lead to structural-wall remodeling, involving gene expression, cell differentiation and growth.…”