Lambride, C. | Search bioRxiv

bioRxiv2026

Blood Pressure Regulates Functional Coupling of L-Type Ca2+ Channels: Reimaging the Foundation of Cerebral Blood Flow Control.

The myogenic response is the key autoregulatory mechanism setting cerebral blood flow and its mechanistic foundation is intimately tied to depolarization and the voltage gating of L-type Ca2+ channels (CaV1.2). While critical, this study argues for an additional mechanism, that of pressure itself enhancing CaV1.2 activity via cooperative gating and perimembrane trafficking of channels subunits. These novel insights were pursued at the cell level using patch-clamp electrophysiology and advanced microscopy, and then functionally in pressurized arteries through measures of tone and intracellular [Ca2+]i. Key findings were confirmed in mutant mice with disrupted functional coupling and translated into arteries procured from human brain tissue. From cerebral blood flow simulations of semi-realistic microvascular networks, we predict that loss of this alternative mechanism leads to maldistribution of brain blood flow and potentially a diminishment of cognitive function. This study reveals previously unrecognized pressure-sensitive CaV1.2 regulatory mechanism that advances understanding of cerebral blood flow. SignificanceBlood pressure sets base arterial constriction - a response critical for blood flow control in brain. This response is tied to CaV1.2 channels and their presumptive and exclusive activation by voltage, reasoning now under great scrutiny. We establish herein with advance methods, a second mode of CaV1.2 pressure regulation, that of enhanced functional cooperativity among neighboring channels. This novel mechano-response is tied to PKC and its ability to set channel phosphorylation and CaV1.2 trafficking. CaV1.2 pressure regulation was observed in human tissues and its disruption (mutant mice) impaired myogenic tone in the presence of preserved voltage control. Cerebral microvascular modeling highlights that losing this mechanism destabilizes blood flow distribution in brain, the knock-on effect being comprised cognitive function.

physiology↗

bioRxiv2025

Loss of Cerebral Autoregulation After Stroke Drives Abnormal Perfusion Patterns

Cerebral autoregulation stabilizes cerebral blood flow (CBF) in response to variations in blood pressure, primarily through dynamic adjustments in arterial caliber. However, the impact of autoregulation mechanisms on local vascular responses and microcirculatory perfusion remains poorly understood. Given that impaired autoregulation is common in pathologies such as ischemic stroke, quantifying vessel-level responses can help to inform clinical strategies. Here, we present a novel in silico model that incorporates static myogenic and endothelial regulatory mechanisms to simulate CBF in large microvascular networks derived from realistic surface vasculatures of mice with and without leptomeningeal collaterals (LMCs). We assessed the role of autoregulation mechanisms under three conditions: i) healthy autoregulation, ii) ischaemic stroke and reperfusion with altered vascular reactivity, and iii) chronic autoregulation dysfunction after stroke. For healthy autoregulation, our model reproduced the classic static autoregulation curve and identified the dominant contribution of surface arteries in buffering pressure changes. Networks with lower descending arteriole density exhibited more extensive arterial dilations, reflecting the topological influence on vessel diameter changes. During reperfusion after stroke, we investigated the interplay between LMCs and parameters governing the vasoreactive response. While LMCs play a crucial role in maintaining residual perfusion in adjacent regions during MCA occlusion, our results suggest that their extent alone does not substantially influence perfusion after recanalization. Instead, alterations in myogenic reactivity emerged as the key contributor to hyperperfusion, underscoring the importance of regulatory mechanisms in determining reperfusion outcomes. To mimic chronic autoregulatory dysfunction, we progressively impaired regulatory capacity in arteries on the middle cerebral artery (MCA) side, reflecting the territory previously affected by stroke. The loss of autoregulation in proximal vessels significantly disrupts capillary perfusion and alters the autoregulation curve. To our knowledge, this is the first in silico study to explore cerebral autoregulation at the microvascular level under both physiological and pathological conditions. Our findings provide mechanistic insight into how individual vessel behavior shapes global flow regulation and highlight myogenic tone as a potential therapeutic target to reduce reperfusion-related complications in stroke.

physiology↗