Abstract
Objective: Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca2+-channels (VGCCs) are involved in the regulation of vasomotor tone. In the present study, we compared arterial and venous responses to flicker stimulation in Cav2.3-competent (Cav2.3[+/+]) and -deficient (Cav2.3[−/−]) mice using retinal vessel analysis.Methods: The mice were anesthetized and the pupil of one eye was dilated by application of a mydriaticum. An adapted prototype of retinal vessel analyzer was used to perform dynamic retinal vessel analysis. Arterial and venous responses were quantified in terms of the area under the curve (AUCart/AUCven) during flicker application, mean maximum dilation (mMDart/mMDven) and time to maximum dilation (tMDart/tMDven) during the flicker, dilation at flicker cessation (DFCart/DFCven), mean maximum constriction (mMCart/mMCven), time to maximum constriction (tMCart/tMCven) after the flicker and reactive magnitude (RMart/RMven).Results: A total of 33 retinal scans were conducted in 22 Cav2.3[+/+] and 11 Cav2.3[−/−] mice. Cav2.3[−/−] mice were characterized by attenuated and partially reversed arterial and venous responses, as reflected in significantly lower AUCart (p = 0.031) and AUCven (p = 0.047), a trend toward reduced DFCart (p = 0.100), DFCven (p = 0.100), mMDven (p = 0.075), and RMart (p = 0.090) and a trend toward increased tMDart (p = 0.096).Conclusion: To our knowledge, this is the first study using a novel, non-invasive analysis technique to document impairment of retinal vessel responses in VGCC-deficient mice. We propose that Cav2.3 channels could be involved in NVC and may contribute to the impairment of vasomotor responses under pathophysiological conditions.
Highlights
As brain tissue lacks significant energy reserves, proper global cerebral blood flow is critical for a constant supply of metabolic substrates, which is achieved through cerebral autoregulation, metabolic feedback mechanisms, and input from the autonomic nervous system [1]
Our results suggest that Cav2.3 channel dysfunction could be associated with altered neurovascular coupling (NVC) in the murine retina and demonstrate how retinal vessel analysis (RVA) can be used for non-invasive in vivo studies on NVC in small animal models
As a measure for the retinal vascular density in both genotypes, we calculated the overall number of vessels leaving the optic nerve head (ONH) in the murine fundus, which amounted to 10.0 (9.5 to 11.0) in Cav2.3[+/+] and 10.0 (10.0 to 10.0) in Cav2.3[−/−] mice (p = 0.486)
Summary
As brain tissue lacks significant energy reserves, proper global cerebral blood flow is critical for a constant supply of metabolic substrates, which is achieved through cerebral autoregulation, metabolic feedback mechanisms, and input from the autonomic nervous system [1]. Much less is known about the exact mechanisms underlying neurovascular coupling (NVC), which mediates continuous adjustment of local cerebral blood flow to dynamic and regionally heterogeneous changes in neuronal activity and metabolic demand. Voltage-gated Ca2+-channels (VGCCs) are critical for Ca2+ influx into all types of cells in the NVU and almost certainly involved in NVC under physiological and pathophysiological conditions [11, 12]. While L-type channels predominate in large caliber proximal vessels, there is growing evidence for a role of nonL-type VGCCs in smaller diameter resistance vessels
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