Cerebral artery myogenic reactivity: The next frontier in developing effective interventions for subarachnoid hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating cerebral event that kills or debilitates the majority of those afflicted. The blood that spills into the subarachnoid space stimulates profound cerebral artery vasoconstriction and consequently, cerebral ischemia. Thus, once the initial bleeding in SAH is appropriately managed, the clinical focus shifts to maintaining/improving cerebral perfusion. However, current therapeutic interventions largely fail to improve clinical outcome, because they do not effectively restore normal cerebral artery function. This review discusses emerging evidence that perturbed cerebrovascular "myogenic reactivity," a crucial microvascular process that potently dictates cerebral perfusion, is the critical element underlying cerebral ischemia in SAH. In fact, the myogenic mechanism could be the reason why many therapeutic interventions, including "Triple H" therapy, fail to deliver benefit to patients. Understanding the molecular basis for myogenic reactivity changes in SAH holds the key to develop more effective therapeutic interventions; indeed, promising recent advancements fuel optimism that vascular dysfunction in SAH can be corrected to improve outcome.

Keywords: Cerebral blood flow; cystic fibrosis transmembrane conductance regulator (CFTR); microvascular dysfunction; myogenic vasoconstriction; tumor necrosis factor.

Figure 1.

The myogenic mechanism underlies the failure of current therapeutic interventions. Shown are schematic tracings of myogenic responses and cerebral autoregulation, as would be observed in the cerebral microcirculation prior to and following subarachnoid hemorrhage (SAH). The myogenic response adjusts vascular resistance proportionally to pressure, resulting in constant flow over a wide range of perfusion pressures. In SAH, myogenic reactivity is augmented: autoregulation persists, but perfusion is reduced. The reduced perfusion in SAH results in secondary ischemic injury. Therapeutic intervention with vasodilators overrides the myogenic response, which compromises autoregulation. Perfusion increases, but pressure is transmitted to the delicate microcirculation, resulting in microvascular injury and edema formation. Therapeutic intervention with “Triple H Therapy” (hypertension, hypervolemia and hemodilution) confers minimal benefit since: (i) within the autoregulatory range, the myogenic response counteracts the pressure increase, resulting in no flow change; or (ii) beyond the autoregulatory range (“breakthrough” pressures), pressure is transmitted to the delicate microcirculation, resulting in microvascular injury and edema formation. Restoring normal myogenic reactivity is the most effective means to improve perfusion without secondary injury.

Figure 2.

Current and proposed molecular mechanisms augmenting myogenic reactivity in subarachnoid hemorrhage. A mechanosensitive complex localized to the plasma membrane initiates the myogenic response, resulting in membrane potential depolarization, calcium entry and extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation. ERK1/2 phosphorylates sphingosine kinase 1 (Sphk1), eliciting its translocation to the plasma membrane and synthesis of sphingosine-1-phosphate (S1P) from sphingosine. Intracellular S1P modulates pressure-stimulated calcium elevation, which activates calmodulin (CAM), myosin light chain kinase (MLCK) and the contraction apparatus. Extracellular S1P activates the S1P₂ receptor subtype (S1P₂R) to activate the RhoA/Rho kinase (ROCK) signaling pathway, which inhibits myosin light chain phosphatase (MLCP). Inhibiting MLCP enhances MLCK's activation of the contractile apparatus. Extracellular S1P is sequestered from S1P₂R by the cystic fibrosis transmembrane conductance regulator (CFTR), which transports S1P across the plasma membrane for dephosphorylation by S1P phosphohydrolase 1 (SPP1). In subarachnoid hemorrhage (SAH), the induction of inflammatory tumor necrosis factor (TNF) signaling curtails CFTR gene expression (not shown) and accelerates CFTR degradation mechanisms: this results in higher S1P bioavailability for S1P₂R signaling and increases activation of the contractile apparatus. In experimental settings, preventing TNF signaling (etanercept; ETN) or antagonizing S1P₂R signaling (JTE013) successfully blocks this pathological process. Therapeutics that increases CFTR expression (Lumacaftor) or activity (Ivacaftor) would be expected to have similar efficacy in terms of blocking the pathological enhancement of S1P/S1P₂R signaling: their value as a therapeutic intervention awaits experimental validation.