Role of the Sympathetic Autonomic Nervous System in Hypoxic Remodeling of the Fetal Cerebral Vasculature

Abstract

Fetal hypoxia triggers compensatory angiogenesis and remodeling through mechanisms not fully elucidated. In response to hypoxia, hypoxia inducible factor drives expression of cytokines that exert multiple effects on cerebral structures. Among these, the artery wall is composed of a heterogeneous cell mix, and exhibits distinct patterns of cellular differentiation and reactivity. Governing these patterns are the vascular endothelium, smooth muscle (SM), adventitia, sympathetic perivascular nerves (SPN) and the parenchyma. Whereas an extensive literature details effects of non-neuronal factors on cerebral arteries, the trophic role of perivascular nerves remains unclear. Hypoxia increases sympathetic innervation with subsequent release of norepinephrine (NE), neuropeptide-y (NPY) and adenosine triphosphate (ATP), which exert motor and trophic effects on cerebral arteries and influence dynamic transitions among smooth muscle phenotypes. Our data also suggests that the cerebrovasculature reacts very differently to hypoxia in fetuses and adults, and we hypothesize that these differences arise from age-related differences in arterial smooth muscle phenotype reactivity and proximity to trophic factors, particularly of neural origin. We provide an integration of recent literature focused on mechanisms by which SPN mediate hypoxic remodeling. Our recent findings suggest that trophic effects of SPN on cerebral arteries accelerate functional maturation through shifts in SM phenotype in an age-dependent manner.

Trophic sympathetic influence weakens pro-contractile role of Cl− channels in rat arteries during postnatal maturation

“…Sympathetic nerves are well-known to have trophic influence on arterial structure and function 17,18 . Arterial sympathetic innervation develops during the first month of postnatal development in rats 8,16 .…”

“…As such a mechanism, we propose here that postnatal reduction in the contribution of Cl − conductance to arterial contraction is associated with trophic influence of sympathetic nerves. This suggestion is based on several findings: (1) the development of sympathetic vasomotor innervation occurs during the first postnatal month in rats 8 , 16 ; (2) sympathetic nerves are known to have trophic influence on arterial structure and function 8 , 17 , 18 ; (3) sympathetic nerves modulate the expression and activity of several ion channels and pumps 19 – 22 ; (4) TMEM16A protein and sympathetic nerves exhibit opposite expression gradients along the vascular tree 23 , 24 . However, experimental evidence for the trophic influences of vascular sympathetic innervation on Cl − channel expression and/or function is not available yet.…”

Pro‐contractile role of chloride in arterial smooth muscle: Postnatal decline potentially governed by sympathetic nerves

“…It has been known for decades that sympathetic nerves exert a trophic influence on vascular structure and function (Adeoye, Silpanisong, Williams, & Pearce, 2015;Bevan, 1984). Importantly, the sympathetic nerves determine smooth muscle cell resting membrane potential and excitability by modulating the expression/activity of ion channels, pumps and cell-to-cell electrical coupling (Abel & Hermsmeyer, 1981;Fleming, 1999;Heumann et al, 2016;Slovut et al, 2004).…”

Simulated Microgravity Induces Regionally Distinct Neurovascular and Structural Remodeling of Skeletal Muscle and Cutaneous Arteries in the Rat

“…Structural and functional changes in the vascular bed could also result from the influence of sympathetic nervous system. In addition to acute control of vessel diameter and blood flow, neurotransmitters from the sympathetic nerves exert a trophic effect on the vasculature (Bevan, 1984;Puzdrova et al, 2014;Adeoye et al, 2015). The severity of trophic sympathetic influence in certain vascular bed may depend on the density of its innervation and/or on the efferent sympathetic traffic it receives.…”