REVIEW Endocrine Cells and Blood Vessels Work in Tandem to Generate
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R59 REVIEW Endocrine cells and blood vessels work in tandem to generate hormone pulses Marie Schaeffer1,2,3,4, David J Hodson1,2,3, Chrystel Lafont1,2,3 and Patrice Mollard1,2,3 1CNRS, UMR-5203, Institut de Ge´nomique Fonctionnelle, F-34000 Montpellier, France 2INSERM, U661, F-34000 Montpellier, France 3Universite´s de Montpellier 1 and 2, UMR-5203, F-34000 Montpellier, France 4Royal college of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland (Correspondence should be addressed to P Mollard who is now at Department of Endocrinology, Institute of Functional Genomics, Montpellier 34094, France; Email: [email protected]) Abstract Hormones are dynamically collected by fenestrated capillaries to generate pulses, which are then decoded by target tissues to mount a biological response. To generate hormone pulses, endocrine systems have evolved mechanisms to tightly regulate blood perfusion and oxygenation, coordinate endocrine cell responses to secretory stimuli, and regulate hormone uptake from the perivascular space into the bloodstream. Based on recent findings, we review here the mechanisms that exist in endocrine systems to regulate blood flow, and facilitate coordinated cell activity and output under both normal physiological and pathological conditions in the pituitary gland and pancreas. Journal of Molecular Endocrinology (2011) 47, R59–R66 Introduction response to metabolic demand, structurally organized populations of endocrine cells that favor coordinated Finely tuned secretion of hormones is essential for responses, and specific mechanisms that permit regulating a multitude of basic body functions such as hormone storage in the perivascular space before growth, metabolism, reproduction, and lactation. The diffusion into the bloodstream (Bonnefont et al. 2005, pulsatile pattern of secretion of most hormones, Nyman et al. 2008, 2010, Hodson et al. 2010, Lafont et al. resulting in burst like or episodic increases in 2010, Sanchez-Cardenas et al. 2010). Since endocrine circulating concentrations, is necessary for the gener- systems must display marked plasticity in response to ation of an appropriate downstream physiological varying physiological demand, these mechanisms must response as well as the regulation of target cell function rapidly and reversibly adapt to the prevailing conditions in both health and disease (Wildt et al. 1981, Matthews (Robinson & Hindmarsh 1999, Islam 2010). Moreover, et al. 1983, Giustina & Veldhuis 1998, Robinson & defaults in hormone levels and their rhythms are Hindmarsh 1999). The generation of hormone pulses signatures of many socioeconomically costly hormonal requires not only the energy demands of thousands of disorders (e.g. diabetes, hypopituitarism and infertility) highly active endocrine cells to be met but also the (Knobil et al. 1994, Carroll et al. 1998, Islam 2010). temporally precise entry of hormone into the blood- Consequently, during the past 50 years, an impressive stream. To achieve this, endocrine cell activity and number of studies have been conducted to understand output has to be temporally correlated with changes in how hormone secretion is regulated and how hormone blood flow, resulting in the replenishment of cell output can be modified/restored to reverse common energy stores and the coordinated passage of hormone hormonal disorders. Despite this, practically nothing into the vasculature. Therefore, organisms have evolved is known about how hormones, locally secreted by mechanisms to tightly regulate blood perfusion and endocrine cells, are captured by fenestrated capillaries oxygenation, coordinate endocrine cell responses to and how blood vessel dynamics contribute to the secretory stimuli, and promote hormone uptake by formation of hormone pulses in the bloodstream. blood vessels. This has prompted recent studies to In light of recent findings (Nyman et al. 2008, 2010, explore whether endocrine systems possess different Lafont et al. 2010), the aims of the current review are to regulatory mechanisms to adjust blood flow velocity in describe the mechanisms which exist in the pituitary Journal of Molecular Endocrinology (2011) 47, R59–R66 DOI: 10.1530/JME-11-0035 0952–5041/11/047–R59 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/24/2021 04:16:28PM via free access R60 M SCHAEFFER and others . Endocrine cells and blood vessels gland and the pancreas to: 1) regulate blood flow to cells needing to respond synchronously to changes in adapt to varying metabolic demand during periods of metabolic demand. In fact, small gaseous molecules, plasticity in hormone release; 2) facilitate coordinated such as oxygen, can freely diffuse from the blood to the cell activity and output; and 3) regulate hormone tissue, following their gradient (Birol et al. 2007). entry into the bloodstream. In addition, we will detail the However, to accommodate the increased metabolic potential role that these mechanisms play in the develop- demand observed in endocrine cells during secretory ment of pathologies related to endocrine dysfunction. episodes, oxygen diffusion may not be rapid enough, and blood flow may require local adjustment to increase delivery. Although proper oxygen supply is essential for endocrine function, very little is known Vascular system about how oxygen intake and consumption are temporally regulated during hormone release in the Structure and common features pituitary. Similarly, the mechanisms by which signaling molecules are distributed to endocrine cells remain Endocrine organs are typically irrigated by a network elusive. The circulation of stimulatory or inhibitory of fenestrated capillaries that allow transendothelial molecules may be restricted by vessel pore size and transit of medium-sized molecules (i.e. incoming secretagogs and released hormones) (Henderson & require additional transport mechanisms. Indeed, Moss 1985). Pancreatic islets, for example, are fenestrations contain a diaphragm composed of radial embedded in a very dense microvascular network, that fibrils converging on a central knob (Bearer & Orci is, almost two- to three-fold denser than in surrounding 1985, Stan et al. 1999), and may act to regulate molecule exocrine tissue (Fig. 1). In addition, endocrine cells in diffusion from the blood to the perivascular space, islets are closely apposed to and polarized toward islet influencing the rate of transcapillary transport of vascular endothelial cells (Bonner-Weir 1988), and hormones toward the bloodstream. The microvascula- produce factors that promote the formation of ture in endocrine organs may therefore, in addition to fenestrae (Lammert et al. 2003). In the pituitary dispersing incoming signaling molecules and clearing gland, blood supply is provided by the hypothalamo- secreted products, function as a gatekeeper that shapes hypophyseal portal vasculature (Harris 1955, Daniel the distribution and the clearance of hormones from 1966, 1976), which ramifies into a specialized perfusion the gland. system to deliver hypothalamic signals to target pituitary cells (Harris 1947). Some pituitary cell types also form Regulation of blood flow topologically organized networks in close apposition to the pituitary vasculature (Bonnefont et al. 2005, Lafont It is generally believed that an increase in endocrine cell et al. 2010). What would be the benefit of such close activity during hormone secretion leads to increased relationships between vasculature and organized cell blood flow to meet metabolic demand. Although the networks? As an example, proximity to highly fene- exact mechanisms remain unclear, release of vasoactive strated vessels may be of considerable advantage for substances most likely plays an important role. During an acute deficit in oxygen supply, the coordinated A B *** release of highly diffusible vasoactive factors, such as 30 nitric oxide (NO), is triggered (Prabhakar 2006, Kemp 25 et al. 2009), inducing changes in mural cell tone. Mural cells, usually vascular smooth muscle cells (VSMC), line 20 vessel walls and regulate blood flow. However, VSMC are 15 absent from the pituitary, and are only found on large efferent arterioles in murine pancreatic islets (Lai et al. 10 2007). Nevertheless, the microvasculature in these Vessels volume (%) volume Vessels 5 tissues possesses specific regulatory mechanisms to 20 µm 0 allow the control of blood flow (Satoh et al. 1989). Endocrine Exocrine Pericytes, another type of mural cell related to VSMC, are putative candidates since they can induce vessel Figure 1 Vessels density in endocrine and exocrine pancreas. (A) Representative image of a mouse pancreatic islet. Green, constriction and modify vascular diameter and blood blood vessels labeled with gelatin-FITC; red, insulin-producing flow (Rucker et al. 2000, Peppiatt et al. 2006). These cells cells. The image corresponds to a 30 mm thick z-projection have been detected in both the pituitary and pancreatic obtained using a Zeiss LSM 510 confocal microscope. islets (Farquhar 1961, Nakamura et al. 1995, Richards (B) Percentage volume occupied by vessels in endocrine and exocrine pancreas measured using Volocity software (Improvi- et al. 2010) and may play an important role in blood sion, Coventry, UK). Statistical analysis was performed by a flow regulation (Gaengel et al. 2009). NO, the main Student’s t-test (***P!0.001). regulator of vascular tone, can be produced by a variety Journal of Molecular Endocrinology (2011) 47, R59–R66