A Novel Neurovascular Liaison Governing the Blood-Brain Barrier

Abstract

How circulating signals enter the median eminence to trigger homeostatic hypothalamic responses is not well understood. Jiang et al. describe a neural mechanism that increases endothelial fenestrations and enhances the hypothalamic response to the circulating hormone leptin, suggesting a novel way to regulate brain entry through vascular wall remodeling.

The pioneering studies of Ehrlich and Goldman first hinted at the existence of a blood-brain barrier (BBB), assumed primarily to shield the brain from circulating toxins and pathogens (Saunders et al., 2014). However, the brain also senses circulating signals arising from the periphery and, through the hypothalamus, generates coordinated neural and hormonal responses aimed at maintaining the homeostasis of the internal environment (Ishii and Iadecola, 2015). The circumventricular organs, regions of the brain with leaky BBB due to holes (fenestrae) in the endothelial cells lining the capillaries, are thought to be the point of access of circulating signals (Kaur and Ling, 2017). The median eminence (ME), one of the circumventricular organs, is particularly well suited for this task since is strategically positioned at the base of the hypothalamus and is closely connected to hypothalamic nuclei and involved in hormonal secretion (Kaur and Ling, 2017). However, it remained unclear whether blood-borne molecules cross ME capillary loops freely, or if their access is controlled by changes in capillary permeability. In this issue of Neuron, Jiang et al. (2020) demonstrate that melanin-concentrating hormone (MCH)-expressing neurons located in the hypothalamus promote the entry of circulating molecules into the ME through neural projections that lead to an increase in capillary fenestrations. The findings provide evidence for a previously unrecognized neurogenic mechanism that controls the access of blood-borne substance into the ME by remodeling capillary structure.

MCH neurons, found in the lateral hypothalamus and zona incerta and projecting widely across the brain, are best known for their role in energy metabolism and sleep (Arrigoni et al., 2019). Jiang et al. (2020) provide several lines of evidence for yet another role for MCH neurons. MCH neurons were found to project to the ME and to make close contacts with tanycytes and fenestrated capillary loops, the main constituents of this brain region (Figure 1). To explore the functional significance of this projection, Jiang et al. (2020) activated MCH neurons chemogenetically in mice in which Evans blue, a plasma protein-bound dye that does not enter the ME, was injected in the circulation to assess microvascular permeability. Chemogenetic activation of MCH neurons induced entry of Evans blue in the ME. Surprisingly, the increase in permeability was not associated with alterations in tight junction complexes of tanycytes, the endfeet of which engage the capillary basal lamina (Kaur and Ling, 2017), but with an increase the number of fenestrations in the capillary loops of the ME.

Figure 1. Regulation of Permeability of Median Eminence Capillary Loops by MCH Neurons.

Melanin concentrating hormone (MCH) neurons projecting to the capillary loops and tanycytes in the median eminence release VEGF, resulting in an increase in the number of fenestrations in endothelial cells and promote the effect of circulating hormones on the hypothalamus.

Since the regulation of energy homeostasis by MCH neurons relies on sensing circulating signals such as the adipocyte hormone leptin, the authors next investigated whether MCH neuron activation enhances the effects of systemic administration of this hormone. Consistent with upregulation of leptin signaling, chemogenetic activation of MCH neurons enhanced STAT3 phosphorylation in the hypothalamic arcuate nucleus and suppressed feeding behavior. To investigate the specific contribution of MCH projections to the ME, the authors used an optogenetic approach in mice. Optogenetic activation of these projections also enhanced capillary permeability and leptin sensitivity, attesting to the specific involvement of MCH neuronal projections to the ME.

Next, the authors investigated whether MCH neurons increased vascular permeability by acting directly on the capillaries or indirectly through the tanycytes. By examining MCH signaling in isolated tanycytes and Ca²⁺ imaging in ME slices, Jiang et al. (2020) did not find evidence that MCH neurons altered signaling in tanycytes, ruling out their participation. However, experiments using phosphoRiboTrap found that MCH neuron activation leads to alteration in mTor signaling not only in neurons and glia, but also in endothelial cells. To identify the signals that could affect endothelial cells, single-nucleus RNA sequencing of MCH neurons identified enrichment of genes involved in vascular endothelial growth factor (VEGF) signaling. Finally, using several complementary approaches, the authors demonstrated that VEGF-A is expressed in MCH neurons and that pharmacological inhibition of VEGF-A signaling attenuated the ability of MCH neurons to enhance the sensitivity to peripheral leptin signaling, implicating this growth factor in the increased ME capillary permeability.

Collectively, Jiang et al. (2020) provide evidence for a novel mechanism whereby MCH neurons increase permeability of the ME through microvascular remodeling mediated by VEGF (Figure 1). Neuronal activation has been previously implicated in the regulation of the BBB, for example by enhancing the brain uptake of IGF-1 (Nishijima et al., 2010) or by increasing water permeability (Raichle et al., 1975). What is remarkable about Jiang et al.’s findings is that neuronal activity leads to structural remodeling of the microvascular wall, resulting in increased fenestration. In the kidney, VEGF regulates endothelial fenestrations, an integral component of the glomerular filtration barrier (Satchell and Braet, 2009). Therefore, similar molecular mechanisms could regulate both glomerular filtration and ME vascular permeability. The findings also raise the possibility that neurovascular projections control the permeability of other circumventricular organs, which also subserve critical homeostatic functions (Kaur and Ling, 2017), and that this mechanism may promotes not only blood-to-brain but also brain-to-blood trafficking of hormones and proteins.

The findings of Jiang et al. (2020) also suggest a new potential mechanism for hypothalamic dysfunction. For example, central leptin resistance is a major cause of obesity (Ishii and Iadecola, 2015). Could disruption of this pathway contribute to leptin resistance by limiting leptin access to the hypothalamus? Hypothalamic dysfunction has also been implicated in neurodegenerative diseases, such as Alzheimer’s disease, and linked to early weight loss, disordered sleep-wake cycle, and hormonal dysfunction that can precede the dementia (Ishii and Iadecola, 2015). Considering the sensitivity of hypothalamic neurons to the pathological effects of amyloid-beta (Ishii et al., 2019), a major culprit in Alzheimer’s disease, could MCH neuronal dysfunction and aberrant permeability of the ME contribute to hypothalamic dysfunction in Alzheimer’s disease? Addressing these questions would require a better understanding of the role of this pathway in normal hypothalamic physiology. The increase in ME vascular permeability was induced with massive MCH neuronal activation. One wonders whether physiological levels of MCH neuronal activity would be sufficient to increase ME vascular permeability and contribute to normal hypothalamic function. Furthermore, how the tanycyte barrier that controls leptin uptake (Balland et al., 2014) is bypassed by MCH activation remains unknown. Despite these outstanding questions, this paper unveils an intriguing neurogenic mechanism capable of capillary wall remodeling and opens exciting new directions in neurovascular biology.