Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors

Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PD-deficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibition-induced expression of miR-1 and contractile proteins was blocked by Rp-β-phenyl-1, N2-etheno-8-bromo-guanosine-3′,5′-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and -independent pathways.

Download Full-text

Aldosterone Promotes Vascular Remodeling by Direct Effects on Smooth Muscle Cell Mineralocorticoid Receptors

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.302854 ◽

2014 ◽

Vol 34 (2) ◽

pp. 355-364 ◽

Cited By ~ 71

Author(s):

Dafina Pruthi ◽

Amy McCurley ◽

Mark Aronovitz ◽

Carol Galayda ◽

S. Ananth Karumanchi ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Remodeling ◽

Mineralocorticoid Receptors ◽

Direct Effects

Download Full-text

Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

eLife ◽

10.7554/elife.42628 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 9

Author(s):

Simon Bulley ◽

Carlos Fernández-Peña ◽

Raquibul Hasan ◽

M Dennis Leo ◽

Padmapriya Muralidharan ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Transient Receptor Potential ◽

Trp Channels ◽

Systemic Blood Pressure ◽

Trp Channel ◽

Systemic Blood ◽

Arterial Smooth Muscle

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout mice for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. Thus, arterial myocyte PKD2 controls systemic blood pressure and targeting this TRP channel reduces high blood pressure.

Download Full-text