Inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signaling in rat aorta smooth muscle cells in response to an agonist of 5-HT2B receptors BW723C86

by Selleckchem | Feb 07 2024

In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-l-arginine (l-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na3VO4) or BVT948. BW723C86 induced a weak rise of [Ca2+]i in the SMC isolated from rat aorta; however, after pre-incubation with Na3VO4 the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N-acetylcysteine and 5-HT2B receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na3VO4 induces oxidative stress in SMC. In the presence of Na3VO4 BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B receptors functional activity.

Comments:

It seems like you're discussing a study that delves into the intricate mechanisms behind serotonin 5-HT2B receptors and their role in blood vessel function. These receptors typically induce relaxation in blood vessels, but under specific conditions, they can lead to vasoconstriction. The study highlights that in hypertensive rats and those with type 2 diabetes, the activation of these receptors by BW723C86, a selective agonist, resulted in aortic contraction.

The shift from relaxation to vasoconstriction might stem from changes in the balance of tyrosine phosphorylation in smooth muscle cells due to oxidative stress. This stress could inhibit protein tyrosine phosphatases (PTPs), potentially unmasking the vasoconstrictive properties of the 5-HT2B receptors.

The study demonstrates that BW723C86, which normally doesn't cause contraction in blood vessel rings, triggered vasoconstriction when PTP inhibitors like sodium orthovanadate (Na3VO4) or BVT948 were present. This effect was linked to increased calcium levels in smooth muscle cells, especially noticeable after pre-incubation with Na3VO4. The heightened response to BW723C86 in the presence of Na3VO4 was affected by various inhibitors, suggesting involvement of protein tyrosine kinase, Src-family kinases, NADPH-oxidase, and reactive oxygen species (ROS). The increase in ROS production due to oxidative stress induced by Na3VO4 appears to amplify the effect of BW723C86 on 5-HT2B receptors.

In summary, the study proposes that oxidative stress inhibits PTP activity, unveiling the vasoconstrictive potential of 5-HT2B receptors. This intricate interplay between oxidative stress, PTP inhibition, and receptor activity underscores the complexity of vascular responses and potentially offers insights into pathological conditions involving vascular dysfunction.