Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

Introduction

Neurovascular coupling (NVC) is a critical process that matches cerebral blood flow (CBF) to neuronal activity, ensuring proper delivery of oxygen and nutrients to brain tissues. The microcirculation, composed of capillaries, arterioles, and venules, plays a central role in this regulation. Endothelial cells (ECs), pericytes, astrocytes, and neurons together orchestrate this finely tuned response, and disruption in any of these components can lead to impaired neurovascular function, contributing to the pathophysiology of various neurological disorders.

Large-pore channels formed by connexins (Cxs) and pannexins (Panxs) have emerged as critical players in intercellular communication within the neurovascular unit (NVU). Cxs form gap junctions (GJs) and hemichannels (HCs), whereas Panxs predominantly form single-membrane channels similar to HCs. These channels are permeable to ions and small signaling molecules such as ATP, glutamate, and other metabolites that modulate vascular tone and cellular responses in the brain. In this review, we discuss the role of connexin and pannexin channels in regulating microcirculatory dynamics and their potential contribution to neurovascular coupling under physiological and pathological conditions.

Connexin and Pannexin Channels in the Neurovascular Unit

The NVU is composed of neurons, astrocytes, ECs, smooth muscle cells (SMCs), pericytes, microglia, and the extracellular matrix. Within this integrated system, connexin and pannexin channels mediate signaling among the various cell types. Connexins are a family of transmembrane proteins that form hexameric hemichannels, which dock with hemichannels of adjacent cells to form gap junctions. Among the twenty-one known human connexins, Cx37, Cx40, Cx43, and Cx45 are prominently expressed in the vasculature.

Pannexins share structural similarities with connexins but do not form classical GJs under physiological conditions. Of the three known pannexins (Panx1, Panx2, and Panx3), Panx1 is the most widely expressed in the brain vasculature. Both Cx- and Panx-based channels have been implicated in the release of ATP, which acts as a key signaling molecule in neurovascular coupling.

Connexin Channels in the Endothelium and Smooth Muscle Cells

ECs and SMCs form an intricate communication network within blood vessels. Connexin-based GJs facilitate the conduction of hyperpolarizing and depolarizing signals across the endothelium and from ECs to SMCs, enabling coordinated vasodilation or vasoconstriction. ECs predominantly express Cx37, Cx40, and Cx43, while SMCs mainly express Cx43 and Cx45. These connexins contribute to myoendothelial junctions (MEJs), specialized contact points between ECs and SMCs that enable the bidirectional exchange of signals.

Disruption of connexin expression or function impairs vascular reactivity and has been associated with hypertension and other vascular pathologies. Studies have shown that genetic deletion of specific connexins leads to altered vascular tone and remodeling. For instance, Cx40-deficient mice exhibit impaired conducted vasodilation, a key mechanism for spreading vasodilation along the vascular tree.

Hemichannels and Pannexin Channels in the Regulation of Vascular Tone

In addition to forming GJs, connexins can function as hemichannels that open in response to various stimuli, including mechanical stress, changes in membrane potential, and inflammatory mediators. Hemichannels allow the release of ATP and other vasoactive molecules into the extracellular space, contributing to the regulation of vascular tone.

Pannexin-1 channels also mediate ATP release and are activated by a range of stimuli, including mechanical stress, increased intracellular calcium, and purinergic receptor activation. In the vascular system, Panx1 is expressed in both ECs and SMCs and participates in the modulation of vasoconstriction and vasodilation.

ATP released through Panx1 channels can activate purinergic P2X and P2Y receptors on adjacent cells, initiating intracellular signaling cascades that influence ion channel activity, calcium dynamics, and cytoskeletal rearrangement. This mechanism plays a vital role in the fine-tuning of vascular responses and in the maintenance of microvascular homeostasis.

Role of Connexins and Pannexins in Neurovascular Coupling

During neuronal activation, glutamate released at synapses stimulates astrocytes, which in turn elevate their intracellular calcium levels and release vasoactive substances, including ATP, nitric oxide (NO), and prostaglandins. Connexin and pannexin channels are involved in both the propagation of calcium waves and the release of these signaling molecules.

Astrocytic Cx43-based hemichannels and Panx1 channels facilitate ATP release into the extracellular space, where it acts on purinergic receptors of nearby ECs and SMCs to modulate vessel diameter. This coordinated action contributes to functional hyperemia—the increase in local blood flow that accompanies neural activity.

Furthermore, endothelial Cx40 and Panx1 have been shown to influence the conduction of vasodilatory signals along arterioles, a process essential for distributing blood flow within the brain. Deficiencies or dysfunctions in these channels have been linked to reduced neurovascular coupling efficiency, particularly in the context of aging and neurodegenerative diseases.

Connexins and Pannexins in Pathological Conditions

Alterations in the expression or function of connexin and pannexin channels have been observed in various pathological conditions, including stroke, traumatic brain injury, Alzheimer’s disease, and epilepsy. Under such conditions, excessive opening of hemichannels or pannexin channels can lead to the release of large amounts of ATP and glutamate, contributing to excitotoxicity, inflammation, and blood-brain barrier (BBB) disruption.

In ischemic stroke, for example, upregulation of Cx43 hemichannels in astrocytes and ECs has been associated with increased permeability of the BBB and infiltration of inflammatory cells. Pharmacological inhibition of hemichannels has been shown to reduce infarct size and improve neurological outcomes in experimental models.

Similarly, in Alzheimer’s disease, aberrant Cx43 and Panx1 activity may exacerbate amyloid-beta-induced vascular dysfunction and neuroinflammation. Targeting these channels represents a potential therapeutic strategy for mitigating vascular contributions to cognitive impairment and dementia.

Conclusion

Connexin and pannexin channels are integral components of the neurovascular unit, playing pivotal roles in intercellular communication, vascular tone regulation, and neurovascular coupling. Through their ability to form gap junctions and hemichannels (in the case of connexins), or large-pore single-membrane channels (in the case of pannexins), they enable the exchange of ions and signaling molecules that are essential for maintaining cerebral blood flow in response to neuronal activity.

Disruption in the normal function of these channels contributes to impaired microcirculation and is implicated in the pathogenesis of numerous neurological disorders. A deeper understanding of the molecular mechanisms governing connexin and pannexin channel activity will not only elucidate their roles in physiological processes but also aid in the Calcium folinate development of novel therapeutic strategies for vascular and neurodegenerative diseases.