In a study published online in Cell Reports, DU Jiulin's group at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences, and the collaborators, created a zebrafish model for in vivo labeling of brain pericytes and systematically explored the developmental dynamics of brain pericytes during the early embryonic stage. The researchers revealed the promoting effect of blood flow on the proliferation of pericytes after ingress into the brain and showed that this process relies on the activation of the mechanosensitive ion channel Piezo1 in vascular endothelial cells (ECs) and its downstream Notch signaling.
Brain function relies on a complex and effective vascular network that provides necessary nutrients and removes waste products. To maintain the homeostasis of neural tissues and normal neural activity, the brain vasculature forms the blood–brain barrier (BBB) during development, strictly controlling substance exchange between blood and brain parenchyma. Abnormalities in the BBB are closely associated with various brain diseases, such as Alzheimer's disease.
Pericytes, as mural cells tightly attached to the outer side of EC tubes in capillaries, play a crucial role in maintaining the integrity of the BBB. Therefore, understanding the development of brain pericytes is essential for studying the formation and maintenance of the BBB. Previous research had indicated that blood flow, the most important functional behavior of blood vessels, participates in regulating the development of brain ECs. However, whether blood flow affects the growth of brain pericytes remained an unexplored question.
To observe the dynamic development of brain pericytes, the researchers employed zebrafish as a vertebrate model and established an in vivo model with specifically marked pericytes using CRISPR/Cas9 gene-editing techniques. The results of long-term time-lapse imaging revealed that brain pericytes originate early from precursor cells on pericerebral blood vessels, and they expand their population largely by proliferation after ingress into the brain. By pharmacologically altering blood flow velocities, the researchers found that blood flow up-regulates pericyte coverage of brain vessels, which is mainly achieved by promoting the proliferation of brain pericytes.
Furthermore, the researchers discovered that the mechanosensitive ion channel Piezo1, expressed on ECs, senses changes in blood flow and mediates the effect of blood flow on pericyte proliferation.
But how exactly is the influence of blood flow transmitted from ECs to pericytes? The researchers observed that the activation of Piezo1 significantly increased the activity of Notch signaling in ECs. In addition, specific enhancement or inhibition of Notch signaling in ECs resulted in corresponding up-regulation or down-regulation of the proliferation frequency of brain pericytes. The researchers observed that increasing blood flow or Piezo1 activity failed to cause a significant change in pericyte coverage of brain vessels when EC Notch signaling was suppressed. These results suggested that EC-intrinsic Notch signaling mediates the regulation of blood flow in the development of brain pericytes, as a downstream effect of Piezo1. Furthermore, by specifically enhancing or inhibiting the outward transmission of Notch signaling in ECs, the researchers provided evidence that the ECs with enhanced Notch signaling directly activated Notch signaling in pericytes, thus promoting their division.
This study uncovers a novel regulatory mechanism for blood flow regulation of brain vascular development and provides new perspectives for understanding brain pericyte development. For researchers actively seeking methods to treat neurological disorders, this study may offer new therapeutic strategies. For example, since up-regulating the activity of Piezo1 or the intensity of Notch signaling in ECs promotes the proliferation of brain pericytes, such up-regulation may be used to improve the function of brain vessels, thus facilitating the recovery of brain function in patients with diseases such as Alzheimer's, vascular dementia, and stroke.
