Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

Abstract

Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.

Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure

“…Thus Tnf −/− and wild-type mice have quantitatively similar myogenic responses (Fig. 1c,d)4519 and systemic haemodynamics20 under non-pathological settings.…”

“…To bypass the compensatory adaptations that occur following germline Tnf gene deletion, we employed a model of acute smooth muscle cell Tnf gene removal (that is, 3 days of tamoxifen treatment in SMMHC- Cre ER T2 mice21 crossed with Tnf flox/flox mice22, generating Sm-TNF-KO45). Although MAP is normal in anaesthetized Sm-TNF-KO mice (Fig.…”

“…Its ubiquitous expression2, however, implies important functions beyond the immune system. Our previous work in cerebral and mesenteric arteries demonstrates that smooth muscle cell-derived TNF is central to the pathological augmentation of myogenic reactivity345; it enables systemic diseases with the ability to alter microvascular autoregulation and hence, local tissue perfusion. Accordingly, sequestering TNF with etanercept (ETN) normalizes pathologically enhanced myogenic responsiveness in cerebral arteries345.…”

“…Our previous work in cerebral and mesenteric arteries demonstrates that smooth muscle cell-derived TNF is central to the pathological augmentation of myogenic reactivity345; it enables systemic diseases with the ability to alter microvascular autoregulation and hence, local tissue perfusion. Accordingly, sequestering TNF with etanercept (ETN) normalizes pathologically enhanced myogenic responsiveness in cerebral arteries345. In mesenteric arteries, however, the same intervention abolishes myogenic reactivity5, fuelling the hypothesis that TNF may serve as a constitutive regulator of myogenic signalling in certain microvascular beds.…”

“…Accordingly, sequestering TNF with etanercept (ETN) normalizes pathologically enhanced myogenic responsiveness in cerebral arteries345. In mesenteric arteries, however, the same intervention abolishes myogenic reactivity5, fuelling the hypothesis that TNF may serve as a constitutive regulator of myogenic signalling in certain microvascular beds. If this observation extends to skeletal muscle resistance arteries, which prominently regulate total peripheral resistance (TPR)6, TNF would emerge as a physiological regulator of mean arterial pressure (MAP).…”