The relationship between cerebrovascular conditions and the onset and/or persistence of headaches has long been a subject of scholarly interest and debate. The vascular theory of headaches was first proposed by Galen in the second century and later revisited by Willis in the late seventeenth century, suggesting that headaches might result from the opening of collateral circulation in brain vessels [11]. However, it was not until the early 1940s that Wolff confirmed the strong link between extracranial vasodilation and migraine [12]. With advancements in basic research and neuroimaging technology, our understanding of the relationship between headaches and vascular conditions has significantly deepened. The following are the potential pathological mechanisms summarized from existing research.

In 1944, the phenomenon of cortical spreading depression (CSD) was observed for the first time in the cortex of rabbits and further confirmed the significant coupling between cerebrovascular dilation and CSD [13]. CSD is a neurophysiological phenomenon wherein regional neurons or glial cells undergo intense depolarization, propagating at a rate of 3–5 mm/min across the cortex to adjacent areas, leading to suppressed neural activity. This process can induce complex changes in cellular fluid and ion distribution, cerebral blood flow, metabolism, and blood–brain barrier permeability [14, 15]. Current data indicate that the hemodynamic response of blood vessels to CSD is heterogeneous and primarily consists of four distinct vascular movements [16, 17]: (i) initial hypoperfusion or vasoconstriction coinciding with direct-current (DC) potential changes; (ii) hyperemia or vasodilation during repolarization, peaking after full recovery of the DC shift; (iii) a smaller-amplitude delayed hyperemia or vasodilation occurring 3–5 min post-CSD; and (iv) reduced blood flow or vasoconstriction observed an hour after CSD (Fig. 1).

The mechanism of cortical spreading depression in headache and cerebrovascular disease

Some evidence suggests that the hemodynamic response induced by CSD may be related to neurotransmitter release mediated by the neurovascular unit (NVU) [18, 19]. The NVU is a complex structure consisting of neurons, astrocytes, endothelial cells, vascular smooth muscle cells (VSMCs), and pericytes (Fig. 1) [20]. This unit is crucial for maintaining brain homeostasis and regulating cerebral blood flow [21]. The dynamic interactions among these cellular components facilitate both neurovascular coupling (NVC) and vasculo-neuronal coupling (VNC), processes essential for adjusting blood flow in response to neuronal activity and maintaining the integrity of the blood–brain barrier (BBB) [20]. Neurons and astrocytes release various vasoactive substances, including nitric oxide (NO), prostaglandins, epoxyeicosatrienoic acids (EETs), glutamate, K+, adenosine, Ca2+, and adenosine triphosphate (ATP), among others (Fig. 1) [22,23,24]. These molecules act on endothelial cells and VSMCs to modulate vascular tone and ensure proper blood supply during neuronal activation. For instance, NO produced by endothelial cells diffuses to VSMCs, causing vasodilation [20]. Astrocytes also contribute by releasing signals like K+ and EETs in response to neuronal activity, further promoting vasodilation through the activation of specific ion channels in endothelial cells and VSMCs [19, 20]. During CSD, the NVU releases numerous vasoactive substances that regulate vascular tone (Fig. 1). This intricate signaling network is vital for the fine-tuning of cerebral blood flow and the overall function of the NVU, with significant implications for neurological health and disease.

Current basic and clinical research indicates a strong correlation between CSD and the aura symptoms of migraines. CSD activates the trigeminovascular system, triggering neuroinflammatory cascades associated with headaches, ultimately leading to their onset [25]. Previous studies have shown that peri-infarct depolarizations, also known as “injury depolarizations,” occur around cerebral infarction sites [14]. These depolarizations often arise in the ischemic penumbra surrounding the infarct core and propagate to adjacent non-ischemic tissue, causing metabolic and hemodynamic changes that exacerbate ischemic damage and affect infarction prognosis [26]. Over the past decade, injury depolarizations have been reported not only in ischemic stroke models but also in conditions such as subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury [27,28,29,30,31]. In addition, depolarization is also an important mechanism of migraine, indicating a potential link between migraine and stroke. Some studies have reported similar conclusions, finding that migraine patients with uncharacteristic foramen ovale have a higher risk of stroke [32]. The complex hemodynamic interactions between CSD or related injury depolarizations and the cerebrovascular system are notable. While CSD typically induces characteristic hemodynamic responses under physiological conditions, its impact is more pronounced under pathological conditions, such as ischemic or hemorrhagic stroke, where CSD leads to significant vasoconstriction and hypoperfusion [27, 33]. Thus, CSD’s regulation of vascular hemodynamic responses may represent a shared neuroelectrophysiological mechanism underlying the pathogenesis of both headaches and cerebrovascular diseases.

Neurogenic inflammation is likely one of the pathological mechanisms behind cerebrovascular-related headaches. When the dura mater receives nociceptive signals, it triggers a neurogenic inflammatory response in the meningeal vessels. This response leads to vasodilation, plasma extravasation, and the release of pro-inflammatory factors from mast cells [34,35,36]. The neuroinflammatory cascade primarily involves endothelial cells, smooth muscle cells, and fibroblasts. There is some evidence indicating that meningeal neurogenic inflammation is a potential pathological mechanism of migraine [37,38,39]. This may be involved in the mechanism of action of cranial and cervical vascular disorders. Endothelial cells not only signal through the release of vasoactive substances but also respond to these signals to maintain vascular homeostasis [40]. When stimulated, vascular system cells release adenosine triphosphate (ATP), which activates purinergic receptors. This activation prompts endothelial cells to release nitric oxide (NO) and pro-inflammatory factors, leading to vasodilation and hyperalgesia [41,42,43]. There is evidence indicating a strong correlation between migraines and the reduction of endothelial progenitor cell counts in cerebral blood vessels [44], the increase of endothelial microparticles [45], and the decrease in urinary NO metabolites [46]. Moreover, research has discovered that the highly selective β2-adrenergic receptor antagonist ICI-118551 can mitigate endothelin-induced hyperalgesia by targeting receptors on endothelial cells [47]. These findings suggest that endothelial cell dysfunction is closely related to headache-associated hyperalgesia. While studies on the role of smooth muscle cells in headaches are limited, recent research has shown that NO can induce vasodilation by activating soluble guanylyl cyclase (sGC) in vascular smooth muscle cells, thereby triggering the NO/cyclic guanosine monophosphatec (GMP) signaling pathway [48]. Additionally, cerebrovascular fibroblasts may play a significant role in the development of headaches by releasing IL-6, which enhances meningeal hypersensitivity [49, 50].

Astrocytes, as crucial elements of the neurovascular unit (NVU), are essential for maintaining cerebral homeostasis and facilitating proper neurovascular coupling (NVC) [51, 52]. Nevertheless, aberrant astrocyte function has been linked to the development of various neurological disorders. This is particularly evident through mechanisms involving neuroinflammation, blood vessel dilation, and NVU dysfunction. Under pathological conditions such as cerebrovascular events, astrocytes transition from a homeostatic state to a reactive, proinflammatory state [53, 54]. This transformation is marked by the release of cytokines like interleukin (IL)-1α, tumor necrosis factor (TNF)-α, and complement component 1q (C1q), which are induced by activated microglia [55,56,57]. Additionally, during cerebrovascular events, there is an increase in astrocytic intracellular Ca2+ levels, often triggered by the heightened activity of channels such as TRPV4 [56, 58,59,60,61]. This dysregulation results in the release of vasoactive substances, including prostaglandins, epoxyeicosatrienoic acids (EETs), and ATP, which in turn alter vascular tone and disrupt normal blood flow regulation [62,63,64]. In summary, the complex interplay between endothelial cells, smooth muscle cells, and fibroblasts, along with the dysfunction of astrocytes contributes significantly to the pathogenesis of cerebrovascular-related headaches and neurovascular disorders through mechanisms of neuroinflammation, blood vessel dilation, and disrupted NVU function (Fig. 2).

The mechanism of neurogenic inflammation in headache and cerebrovascular disease

Stephen et al. were the first to propose that migraine is a disorder of the sympathetic nervous system (SNS) [65]. This hypothesis posits that stress, the most common trigger for migraines, activates the SNS. The overactivation of the SNS and the release of noradrenaline (NE) affect the α-adrenergic receptors on blood vessels, causing constriction of the extracranial arteries and leading to the prodromal symptoms of migraine [66]. However, with prolonged SNS activation, the levels of vasoconstrictive neurotransmitters like NE gradually decrease, while the levels of vasodilatory substances such as dopamine, adenosine, and prostaglandins increase, resulting in the dilation of extracranial arteries and triggering the migraine attack.

The regulation of the vasomotor function of the extracranial arteries by the SNS operates through the following mechanisms: the meningeal arteries receive perivascular innervation from the superior cervical ganglion, the sphenopalatine ganglion, the otic ganglion, the internal carotid ganglion, and the trigeminal ganglion [67]. These perivascular nerves are directly connected to the arteries, thereby modulating their vasomotor function. The superior cervical ganglion, being a sympathetic ganglion, releases peripheral vasoconstrictive substances such as noradrenaline and neuropeptide Y [68]. In contrast, the sphenopalatine, otic, and internal carotid ganglia are parasympathetic ganglia that release peripheral vasodilatory substances like acetylcholine, vasoactive intestinal peptide (VIP), and nitric oxide synthase (NOS) [69, 70]. When the sympathetic nervous system is activated, it causes constriction of the meningeal arteries, particularly those with larger diameters [71]. Under normal physiological conditions, the SNS has a minimal impact on the function of the nociceptive sensory system. However, in inflammatory tissues or cases of chronic nerve injury, the influence of sympathetic innervation on nociceptive fibers becomes significantly pronounced [72]. Enhanced sympathetic–sensory coupling, resulting from nerve injury, leads to upregulation of adrenergic receptors [73], sprouting of sympathetic fibers [74], and increased efferent excitability [75], all of which indicate that the SNS plays a role in the generation, transmission, and modulation of pain.

Therefore, acute stress events caused by ischemia, hemorrhage, and vascular malformations in the head and neck, as well as chronic nerve injuries due to vasculitis and chronic intracranial vascular diseases, may lead to SNS dysfunction. This dysfunction is potentially one of the pathophysiological mechanisms underlying cerebrovascular-related headaches.

The trigeminal vascular system is an important mechanism for diseases such as migraine and cluster headache [76, 77]. The meningeal vessels, as an important part of the trigeminal vascular system, can expand blood vessels and produce vasoactive substances, thereby promoting the production of a large number of damaging signals, including plasma protein extravasation, increased permeability of the blood–brain barrier, and the production of calcitonin gene-related peptide (CGRP), VIP, substance P (SP), pituitary adenylate cyclase-activating peptide (PACAP), and nitric oxide synthase (NOS) (Fig. 3) [78, 79]. The activated neurons in this area stimulate the production of more CGRP, which is transmitted to the surrounding blood vessels to amplify the effects of damaging signals. Additionally, CGRP reaches the central nervous system, activating neurons in the spinal trigeminal nucleus caudalis (TNC) and microglia, which in turn promote the production of inflammatory substances like IL-1β and brain-derived neurotrophic factor (BDNF), leading to continued abnormal electrical activity in the neurons (Fig. 3) [80, 81]. Recent evidence suggests that the trigeminal vascular system serves as a potential mechanism linking headache and vascular disease [78, 82]. Alterations such as vasodilation, increased blood–brain barrier permeability, and the release of inflammatory mediators within this system are fundamental to the pathogenesis of primary headaches like migraine [83,84,85]. These same mechanisms may also contribute to the progression of cerebrovascular diseases. It is worth mentioning that the interaction between microglia and neurons is one of the key links in the abnormal dilation of blood vessels and the induction of harmful signals to continue to upload to higher centers [86]. This promotes the chronic development of damaging signals and continues to transmit them to higher-level centers, including the rostral ventromedial medulla, locus coeruleus (LC), and periaqueductal gray of the brainstem [87,88,89,90]. However, the nociceptive signal does not stop, but continues to be transmitted to the nuclei of the hypothalamus and thalamus, and finally conveyed to the cerebral cortex (including the motor cortex [MC], sensory cortex [SC], and visual cortex [VC], etc.) [87, 91, 92]. After receiving nociceptive signal stimulation, the various higher cortical centers may be connected with each other, but the specific mechanism is not clear. When the cortex of the brain is subjected to continuous damaging signals, it sends protective instructions downward [92]. However, the gradual buildup of chronic damaging signals disrupts the balance between the propagation of these signals and their inhibition. This imbalance triggers an inflammatory cascade around the meningeal vessels and abnormal neuron activation in various brain regions, leading to acute headache attacks and chronic progression [38,