Abstract
We recently reported that the myogenic responses of the renal afferent arteriole (Af-Art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow (RBF and CBF) were impaired in Fawn Hooded hypertensive (FHH) rats and were restored in a FHH.1BN congenic strain in which a small segment of chromosome 1 from the Brown Norway (BN) containing 15 genes including dual-specificity protein phosphatase-5 (Dusp5) were transferred into the FHH genetic background. We identified 4 single nucleotide polymorphisms in the Dusp5 gene in FHH as compared with BN rats, two of which altered CpG sites and another that caused a G155R mutation. To determine whether Dusp5 contributes to the impaired myogenic response in FHH rats, we created a Dusp5 knockout (KO) rat in the FHH.1BN genetic background using a zinc-finger nuclease that introduced an 11 bp frame-shift deletion and a premature stop codon at AA121. The expression of Dusp5 was decreased and the levels of its substrates, phosphorylated ERK1/2 (p-ERK1/2), were enhanced in the KO rats. The diameter of the MCA decreased to a greater extent in Dusp5 KO rats than in FHH.1BN and FHH rats when the perfusion pressure was increased from 40 to 140 mmHg. CBF increased markedly in FHH rats when MAP was increased from 100 to 160 mmHg, and CBF was better autoregulated in the Dusp5 KO and FHH.1BN rats. The expression of Dusp5 was higher at the mRNA level but not at the protein level and the levels of p-ERK1/2 and p-PKC were lower in cerebral microvessels and brain tissue isolated from FHH than in FHH.1BN rats. These results indicate that Dusp5 modulates myogenic reactivity in the cerebral circulation and support the view that a mutation in Dusp5 may enhance Dusp5 activity and contribute to the impaired myogenic response in FHH rats.
Highlights
The myogenic response is an intrinsic property of vascular smooth muscle cells (VSMC) that initiates contraction of arterioles in response to elevations in transmural pressure [1,2] and contributes to autoregulation of renal and cerebral blood flow (RBF, CBF). [3,4,5,6] We recently reported that the myogenic responses of the renal afferent arteriole (Af-Art) and middle cerebral artery (MCA) and autoregulation of RBF and CBF were impaired in Fawn Hooded hypertensive (FHH) rats and were restored in a FHH.1BN congenic strain in which a small segment of chromosome 1 from the Brown Norway (BN) containing 15 genes, including dual-specificity protein phosphatase-5 (Dusp5) were transferred into FHH genetic background. [7,8,9] the genes that contribute to the impaired myogenic response and the mechanisms involved remain to be determined
We recently reported that the myogenic response of the MCA and autoregulation of CBF were markedly impaired in FHH rats and were restored in a FHH.1BN congenic strain in which Chromosome 1 from the BN rats containing 15 genes was transferred into the FHH genetic background. [7,8,9] the gene or genes that contribute to the impairment of vascular function and the mechanisms involved still remain obscure
To determine if the altered CpG sites and/or the G155R mutation might underlie the loss of the myogenic response in FHH rats, we created Dusp5 KO rats in the FHH.1BN genetic background using Zinc-finger nuclease (ZFN) KO technology [25,26,27,39]
Summary
Dusp is a serine-threonine phosphatase that inactivates MAPK activity[10,11,12,13,14] by dephosphorylating ERK1/2 MAP kinases [15] which modulate the activities of the large conductance Ca2+activated K+ channel (BK) and transient receptor potential (TRP) channels. Both of these channels influence vascular reactivity and the myogenic response. We investigated whether there are differences in the expression of p-ERK1/2 in cerebral microvessels isolated from these strains as they are the primary substrates normally dephosphorylated and inactivated by Dusp5 [15,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
