Perivascular Innervation: A Multiplicity of Roles in Vasomotor Control and Myoendothelial Signaling

Abstract

The control of vascular resistance and tissue perfusion reflect coordinated changes in the diameter of feed arteries and the arteriolar networks they supply. Against a background of myogenic tone and metabolic demand, vasoactive signals originating from perivascular sympathetic and sensory nerves are integrated with endothelium-derived signals to produce vasodilation or vasoconstriction. PVNs release adrenergic, cholinergic, peptidergic, purinergic, and nitrergic neurotransmitters that lead to SMC contraction or relaxation via their actions on SMCs, ECs, or other PVNs. ECs release autacoids that can have opposing actions on SMCs. Respective cell layers are connected directly to each other through GJs at discrete sites via MEJs projecting through holes in the IEL. Whereas studies of intercellular communication in the vascular wall have centered on endothelium-derived signals that govern SMC relaxation, attention has increasingly focused on signaling from SMCs to ECs. Thus, via MEJs, neurotransmission from PVNs can evoke distinct responses from ECs subsequent to acting on SMCs. To integrate this emerging area of investigation in light of vasomotor control, the present review synthesizes current understanding of signaling events that originate within SMCs in response to perivascular neurotransmission in light of EC feedback. Though often ignored in studies of the resistance vasculature, PVNs are integral to blood flow control and can provide a physiological stimulus for myoendothelial communication. Greater understanding of these underlying signaling events and how they may be affected by aging and disease will provide new approaches for selective therapeutic interventions.

Integration and Modulation of Intercellular Signaling Underlying Blood Flow Control

“…Indeed, the original observation of spreading vasodilatation in the web of the frog hindlimb was attributed to a local axon reflex [26]. While defining regional variation in the nature of innervation among vascular beds and animal species, ensuing publications have confirmed cholinergic, nitroxidergic, purinergic and sensory as well as adrenergic (i.e., sympathetic) innervation of the microvasculature (reviewed in [27]).…”

Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function

“…This process of dynamic blood flow regulation requires that endothelial activation and production of vasodilation rapidly counteract basal activation of SMC adrenoreceptors along resistance networks in accord with metabolic demand (3, 5). Despite widespread distribution of perivascular sympathetic nerves along arteriolar networks of skeletal muscle (46, 47), vasoconstriction via norepinephrine stimulation of SMC adrenoreceptors may be restricted to distinct sites, whereas vasodilatory signals emitted by ECs require coordination over millimeter distances (3). A basis for such differential regulation of electrical signals between SMCs (“discrete”) and ECs (“conducted”) can be inferred from the kinetics and magnitude of dilatory responses that propagate from pre-capillary arterioles to extraparenchymal feed arteries (i.e., “rapid onset vasodilation”) following contraction of mouse gluteus maximus skeletal muscle in vivo (48).…”

“…A basis for such differential regulation of electrical signals between SMCs (“discrete”) and ECs (“conducted”) can be inferred from the kinetics and magnitude of dilatory responses that propagate from pre-capillary arterioles to extraparenchymal feed arteries (i.e., “rapid onset vasodilation”) following contraction of mouse gluteus maximus skeletal muscle in vivo (48). Further, depending on other major vascular types of focus (e.g., mesenteric arteries), there may be additional perivascular nerve types (e.g., sensory) and respective transmitters (e.g., calcitonin gene related peptide) present to further influence the cell specific handling of electrical signals (47, 49). It is anticipated that a rigorous examination of the role of perivascular nerves in navigating cross-talk between SMCs and ECs will be accomplished using complex electrophysiology methods in the near future.…”

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

“…Little is known about the relationships between mitochondrial membrane potential and NOS activation in other cell types of the neurovascular unit such as cortical neurons and perivascular nerves. Substances such as NO could be produced by cortical neurons or perivascular nerves and promote relaxation of cerebral vascular smooth muscle (41). Cerebral arteries are heavily invested by NOS-containing perivascular nerves and are closely associated to parenchymal neurons (1,39,40).…”