Single-capillary endothelial dysfunction resolved by optoacoustic mesoscopy.

Microvascular endothelial dysfunction (MiVED) is an early marker of endothelial impairment, often preceding dysfunction in large arteries. Although MiVED assessment could reveal new insights into the pathophysiology of cardiovascular disease (CVD) or offer earlier detection and finer disease stratification, detailed in-vivo MiVED observation remains challenging due to a lack of suitable technologies. To address this gap, we hypothesized that accelerating ultra-wideband raster-scan optoacoustic mesoscopy (RSOM), i.e., fast RSOM (fRSOM), could resolve for the first time cutaneous MiVED features at single capillary resolution. We investigated whether we could record morphological features and dynamic responses during post-occlusive reactive hyperemia to achieve the most detailed observation of microvascular endothelial function to date. Our results show that using fRSOM on skin clearly measured the effects of smoking (N = 20) and atherosclerotic CVD (N = 20) on cutaneous endothelial function. For the first time, we found layer-specific effects, with smoking and CVD affecting the sub-papillary dermis differently than the reticular dermis; a finding not resolvable using "bulk" volumetric signals from laser Doppler flowmetry or tissue spectrometry. Interestingly, we observed no substantial structural changes in the microvasculature of smokers and volunteers with CVD, indicating that MiVED may be an earlier marker than morphology-based biomarkers typically assessed by histological studies. Our study introduces a non-invasive modality that enables the visualization and quantification of skin microvascular structure and function, bridging a technological gap and offering new insights into the effects of diseases on MiVED. This study potentially paves the way for fRSOM use as an early detection, diagnostic, or theranostic marker.