Blood pressure homeostasis is maintained by a P311–TGF-β axis
Kameswara Rao Badri, … , Kenneth L. Byron, Lucia Schuger
Kameswara Rao Badri, … , Kenneth L. Byron, Lucia Schuger
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4502-4512. https://doi.org/10.1172/JCI69884.
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Blood pressure homeostasis is maintained by a P311–TGF-β axis

Abstract

P311 is an 8-kDa intracellular protein that is highly conserved across species and is expressed in the nervous system as well as in vascular and visceral smooth muscle cells. P311-null (P311–/–) mice display learning and memory defects, but alterations in their vasculature have not been previously described. Here we report that P311–/– mice are markedly hypotensive with accompanying defects in vascular tone and VSMC contractility. Functional abnormalities in P311–/– mice resulted from decreased total and active levels of TGF-β1, TGF-β2, and TGF-β3 that arise as a specific consequence of decreased translation. Vascular hypofunctionality was fully rescued in vitro and in vivo by exogenous TGF-β1–TGF-β3. Conversely, P311-transgenic (P311TG) mice had elevated levels of TGF-β1–TGF-β3 and subsequent hypertension. Consistent with findings attained in mouse models, arteries recovered from hypertensive human patients displayed increased P311 expression. Thus, we identified P311 as the first protein known to modulate TGF-β translation and the first pan-regulator of TGF-β expression under steady-state conditions. Together, our findings point to P311 as a critical blood pressure regulator and establish a potential link between P311 expression and the development of hypertensive disease.

Authors

Kameswara Rao Badri, Ming Yue, Oscar A. Carretero, Sree Latha Aramgam, Jun Cao, Stephen Sharkady, Gene H. Kim, Gregory A. Taylor, Kenneth L. Byron, Lucia Schuger

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Figure 4

Administration of recombinant TGF-βs restores blood pressure as well as vascular muscle tone, contractility, and RhoA activity to P311–/– mice.

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Administration of recombinant TGF-βs restores blood pressure as well as ...
(A) ELISA showing total and active TGF-βs in blood serum of WT and P311–/– mice (n = 4 per group), treated or not with rTGF-β1-3. (B) Plethysmographic blood pressure determination (n = 5 per group), with and without rTGF-β1-3 treatment. (C) Echocardiographic aortic diameter in conscious mice (n = 5 per group) at basal levels and after treatment with rTGF-β1-3 or vehicle. (D) Contractile response of mouse aortas (n = 5 per group) to increasing K+ concentration, with and without rTGF-β1-3 treatment. (E) RhoA activity assay showing total and active RhoA in mouse aortas (n = 3 per group), with and without rTGF-β1-3 treatment. Relative density of total and active RhoA is also shown. (F) Collagen gel contraction by mouse aorta–derived VSMCs, with and without rTGF-β1-3 treatment. Relative contraction is also shown, calculated as percent decrease in collagen gel diameter from the original diameter. Gel contraction data were collected from triplicate wells. Data represent mean ± SD. *P < 0.05, **P < 0.01, 1-way ANOVA.