Pharmacological Activation of NO-Sensitive Guanylyl Cyclase Ameliorates Obesity-Induced Arterial Stiffness
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Objective
Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) 1 and dementia 2 . Akin to anti-hypertensive and lipid-lowering drugs, arterial de-stiffening therapies could be beneficial at decreasing CVD risk. We previously discovered that enhanced cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributes to increased arterial stiffness 3 . In aortas and VSMCs, we previously found that decreased NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, caused downregulation of cGMP-dependent protein kinase I (cGKI) and of its target vasodilator-stimulated phosphoprotein (pVASP S239 ), leading to increased cytoskeletal actin polymerization 3 . In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP S239 and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness.
Approach & Results
Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness 4 , (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure, (2) increased aortic pVASP S239 levels, and (3) decreased the ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASP S239 levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), used to mimic the inflammatory milieu of HFHS aortas. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI SMKO ), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP, 1 μmol/L), which also decreased VSMC stiffness in vitro .
Conclusions
Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.
