Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets

Abstract

Pancreatic islets are highly vascularized micro-organs ensuring whole body glucose homeostasis. Islet vascular cells play an integral part in sustaining adequate insulin release by beta cells. In particular, recent studies have demonstrated that islet pericytes regulate local blood flow velocity and are required for maintenance of beta cell maturity and function. In addition, increased metabolic demand accompanying obesity alters islet pericyte morphology. Here, we sought to explore the effects of metabolic stress on islet pericyte functional response to stimulation in a mouse model of type 2 diabetes, directly in the pancreas in vivo . We found that high fat diet induced islet pericyte hypertrophy without alterations in basal local blood flow. However, optogenetic stimulation of pericyte activity revealed impaired islet vascular responses, despite increased expression of genes encoding proteins directly or indirectly involved in cell contraction. These findings suggest that metabolic stress impinges upon islet pericyte function, which may contribute to beta cell failure during T2D.

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

“…In mice, pericytes provide direct trophic support for beta cells, contributing to their proliferation, maturation and insulin secretion (18)(19)(20)(21), or indirectly by participating in ECM synthesis (22). Pericytes may also impact beta cell health and function by maintaining proper blood supply to endocrine cells as they are important regulators of islet capillary diameter and blood flow (17,23,24). Importantly, pericyte-mediated changes in islet blood flow are required for proper islet hormone secretion and glucose homeostasis in mice (25) .…”

“…Changes in islet pericyte density, morphology and function occur under pathophysiological conditions. In mouse models of type 2 diabetes, for instance, islet pericytes enlarge and adopt a myofibroblast-like appearance (15, 26, 27), which interferes with their capacity to regulate islet blood flow (24). Although pericytes have important physiological and pathophysiological functions in islets, it is not known what happens to this cell population during T1D development.…”

Median eminence blood flow influences food intake by regulating ghrelin access to the metabolic brain

“…In addition, α-SMA labels contractile pericytes on capillaries ( 12 , 27 , 28 ). Second, NG2 is expressed in morphologically distinct arteriolar smooth muscle cells, also expressing α-SMA ( 14 , 35 ). Finally, NG2 is expressed in oligodendrocyte precursor cells (OPCs), also called NG2-glia ( 36 ).…”

“…It has been shown that pericytes are electrically responsive, enabling optogenetic control of their activity ( 14 , 27 , 28 , 35 ). In accordance with a role for pericytes in blood flow regulation described previously in the cerebellum ( 13 ) and the cortex ( 12 ), manipulation of NG2-positive cell activity through optogenetic stimulation in vivo was able to modify blood flow in the ME.…”

“…The ME microvasculature is composed of arterioles and capillaries, lined by contractile smooth muscle cells and pericytes, respectively (11). Pericytes have attracted increasing interest due to their role in regulating capillary blood flow (12)(13)(14), BBB integrity (15), and vascular permeability to circulating leptin (16). In addition, pericytes are implicated in the sustained blood flow decrease in the brain following ischemia and stroke (17), development of pathologies such as cerebral arteriopathy (18,19) and diabetic retinopathies (20).…”