Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway

Abstract

BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.

Occluded Superior Mesenteric Artery and Vein. Therapy with the Stable Gastric Pentadecapeptide BPC 157

“…Of note, it remains to be fully specified how 'endothelium maintenance → epithelium maintenance' may go to the advanced 'endothelium maintenance → epithelium maintenance = blood vessel recruitment and activation' ('running') towards the site of injury, also described as 'bypassing' the occlusion via alternative pathways and to resolving the simultaneous permanent occlusion of a vein and artery. As mentioned previously, endothelium protection may be immediate, as shown with the maintenance of endothelium function to counteract stomach mucosal lesions when exposed to absolute alcohol [20,30], combined with a direct effect on vasomotor tone [29] and ischemia-induced increased capillary permeability [37]. Part of this defensive pathway, which needs to be fully determined, may be the already mentioned BPC 157 effects: activation of the Src-caveolin-1-eNOS pathway [29], activation of the VEGFR2-Akt-eNOS signalling pathway without the need of other known ligands or shear stress [33] and membrane stabilisation [37].…”

“…As mentioned previously, endothelium protection may be immediate, as shown with the maintenance of endothelium function to counteract stomach mucosal lesions when exposed to absolute alcohol [20,30], combined with a direct effect on vasomotor tone [29] and ischemia-induced increased capillary permeability [37]. Part of this defensive pathway, which needs to be fully determined, may be the already mentioned BPC 157 effects: activation of the Src-caveolin-1-eNOS pathway [29], activation of the VEGFR2-Akt-eNOS signalling pathway without the need of other known ligands or shear stress [33] and membrane stabilisation [37]. Counteracting leaky gut syndrome, via increased tight junction protein ZO-1 expression and transepithelial resistance [37], would avoid a shift of fluid and proteins from the intravascular to the extravascular space and thus prevent an increase in intra-abdominal pressure [27].…”

“…Due to the interaction among the three body cavities, the increased intra-abdominal pressure leads to increased intracranial pressure and vice versa [27]. The fact that BPC 157 can inhibit the mRNA expression of inflammatory mediators (iNOS, IL-6, IFNγ, and TNF-α) as well as increase protein expression of HSP70, HSP90 and promote the expression of antioxidant proteins, such as HO-1, NQO-1, glutathione reductase, glutathione peroxidase 2 and GST-pi [37] indicate that this peptide interacts with several molecular pathways [5,25,29,[31][32][33][34][35][36][37]. BPC 157 also has a modulatory role on the NO system and NO agents [3,4,28,30], in particular, on blood pressure [30] and thrombocyte function [22][23][24].…”

“…The nitric oxide (NO) system also plays a crucial role in the effects of BPC 157 on the endothelium [28]. BPC 157 regulates vasomotor tone through specific activation of the Srccaveolin-1-endothelial nitric oxide synthase (eNOS) pathway [29], and it has a modulatory role [3,4,28] for blood pressure [30] and maintaining thrombocyte function [22][23][24]. BPC 157 also interacts with several molecular pathways [5,25,29,[31][32][33][34][35][36][37] and may be a free radical scavenger to counteract reperfusion-induced oxidative injury [5,6,[8][9][10][11][12][36][37][38][39][40].…”

“…BPC 157 regulates vasomotor tone through specific activation of the Srccaveolin-1-endothelial nitric oxide synthase (eNOS) pathway [29], and it has a modulatory role [3,4,28] for blood pressure [30] and maintaining thrombocyte function [22][23][24]. BPC 157 also interacts with several molecular pathways [5,25,29,[31][32][33][34][35][36][37] and may be a free radical scavenger to counteract reperfusion-induced oxidative injury [5,6,[8][9][10][11][12][36][37][38][39][40]. BPC 157 acts as a membrane stabiliser, counteracting leaky gut syndrome by interacting with several molecular pathways [37]; thereby, its curative effect involves modulating ischemia-induced increased capillary permeability [37].…”