Pericyte control of pancreatic islet blood flow impacts glucose homeostasis

Tamayo, Alejandro; Gonçalves, Luciana Mateus; Rodriguez-Diaz, Rayner; Pereira, Elizabeth; Canales, Melissa; Caicedo, Alejandro; Almaça, Joana

doi:10.1101/2021.08.24.457539

Cited by 3 publications

(10 citation statements)

References 42 publications

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“…Although a 200 µm diameter fiber optic was used to activate ChR2, we cannot exclude some off target effects on smooth muscle cells. Notably, manipulation of pericyte activity through optogenetic stimulation in vivo reduced local blood flow, consistent with previous reports ( 16 , 17 ). This was unlikely due to local heating effects or damage, since termination of laser stimulation allowed blood flow to recover.…”

Section: Discussionsupporting

confidence: 92%

“…We first sought to investigate alterations in islet pericyte morphology following HFD feeding. We used mice expressing DsRed under the control of the NG2 promoter (NG2DsRed) ( 16 , 30 , 37 ), since NG2DsRed cells extensively cover islet capillaries ( Figure 1A ) ( 16 , 17 ). We found that most NG2DsRed cells expressed the pericyte marker platelet-derived growth factor receptor beta (PDGFRβ) ( Figure S1A ) ( 16 ), and a subset of them also expressed the contractile smooth muscle actin protein (αSMA) ( Figure S1A ), consistent with previous studies that described the heterogeneous nature of the pericyte population in islets ( 16 , 17 ).…”

Section: Resultsmentioning

confidence: 99%

“…We used mice expressing DsRed under the control of the NG2 promoter (NG2DsRed) (16,30,37), since NG2DsRed cells extensively cover islet capillaries (Figure 1A) (16,17). We found that most NG2DsRed cells expressed the pericyte marker platelet-derived growth factor receptor beta (PDGFRb) (Figure S1A) (16), and a subset of them also expressed the contractile smooth muscle actin protein (aSMA) (Figure S1A), consistent with previous studies that described the heterogenous nature of the pericyte population in islets (16,17). Consistent with previous studies (32,(41)(42)(43), male mice fed HFD for 16 weeks presented with obesity, hyperglycemia, glucose intolerance, insulin resistance, defective glucose-stimulated insulin release (GSIS), and changes in islet gene expression such as Ins1, Ins2 and Gck (Figure S1B-H), as expected.…”

Section: Hfd Alters Islet Pericyte Morphology and Densitymentioning

confidence: 99%

“…In addition, islet pericytes are significant sources of islet basement membrane components, essential for beta cell function ( 13 , 14 ). Finally, although different vasoactive factors, nutrients and hormones ( 15 ), including insulin ( 5 ) have long been known to regulate islet blood flow, such regulation was thought to mainly occur at the pre-capillary level ( 3 ), and a direct role for pericytes in islet blood flow regulation was recently demonstrated ( 16 , 17 ), providing another level of control in addition to those of feeding arterioles. Indeed, cytosolic calcium changes in response to glucose and vasoactive molecules produced by beta cells, endothelial cells and sympathetic nerves allow islet pericytes to adjust capillary diameter ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…Since both blood flow direction and velocity within islets are important for islet function ( 18 , 19 ), it was hypothesized that pericytes may contribute to glucose homeostasis through the active control of islet blood supply. Recent work using islets implanted in the anterior chamber of the eye of streptozotocin-treated diabetic mice, indeed showed that pericytes control of blood flow in islets alone is able to regulate adequate hormone secretion and systemic blood glucose levels ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Hfd Alters Islet Pericyte Morphology and Densitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets

et al. 2022

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

Romanò¹,

Lafont²,

Campos³

et al. 2023

JCI Insight

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Central integration of peripheral appetite-regulating signals ensures maintenance of energy homeostasis. Thus, plasticity of circulating molecule access to neuronal circuits involved in feeding behavior plays a key role in the adaptive response to metabolic changes. However, the mechanisms involved remain poorly understood despite their relevance for therapeutic development. Here, we investigated the role of median eminence mural cells, including smooth muscle cells and pericytes, in modulating gut hormone effects on orexigenic/anorexigenic circuits. We found that conditional activation of median eminence vascular cells impinged on local blood flow velocity, and altered ghrelin-stimulated food intake by delaying ghrelin access to target neurons. Thus, activation of median eminence vascular cells modulates food intake in response to peripheral ghrelin by reducing local blood flow velocity and access to the metabolic brain.

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<b>Efficient vascular and neural engraftment of stem cell-derived islets</b>

Thorngren,

Brboric,

Vasylovska

et al. 2024

Preprint

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<p dir="ltr">Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at three months post-transplantation, and observed that the cell apoptosis rates were lower, but the vascular density was similar in SC-islets to that of human islets. While the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. The oxygenation of the SC-islet grafts was twice as high as in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, also the reinnervation of the SC-islets was four- to five-fold higher than the human islets. Both SC-islets and the human islets contained amyloid at one and three months post-transplantation. We conclude that the vascular and neural engraftment of SC-islets is superior to human islets, but that grafts of both origins develop amyloid with potential long-term consequences.</p>

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Pericyte control of pancreatic islet blood flow impacts glucose homeostasis

Cited by 3 publications

References 42 publications

Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets

Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets

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

<b>Efficient vascular and neural engraftment of stem cell-derived islets</b>

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