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Editor—Summer Leaf
Antipsychotic drugs are widely used in psychiatry and medical fields, and have become the main drug class for the treatment of mental disorders, showing significant effects in the treatment of schizophrenia, delusional disorder and depression [1].
Although these agents are licensed for clinical use and safe for most patients, there are unknown side effects [2-4].
Hematopoietic stem and progenitor cells (HSPCs) have the differentiation potential
to differentiate into mature blood cells.
In adult mammals, hematopoietic stem/progenitor cells are mainly found in hematopoietic organs such as bone marrow, liver, and spleen [5].
The survival, self-renewal, and proliferation of hematopoietic stem/progenitor cells are regulated by their organ microenvironment [6].
The vascular microenvironment is one of
the most important microenvironments of hematopoietic stem/progenitor cells.
However, the effect of antipsychotic drugs on hematopoiesis and the vascular microenvironment of organs is still unclear
.
Liu Yang's research group of the School of Medicine of South China University of Technology and Chen Qi's research group of Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, found that antipsychotic drugs cause vascular abnormalities
in hematopoietic organs on experimental animals.
Recently, the results were published in The FASEB Journal under the title "Antipsychotic drugs induce vascular defects in hematopoietic organs.
"
The study showed that antipsychotic drugs represented by haloperidol affected homeostasis hematopoiesis in mice and caused vascular malformations in hematopoietic organs including bone marrow, spleen, and liver, but had no effect on
blood vessels of non-hematopoietic organs 。 Hematopoietic abnormalities and vasodilation caused by drugs such as haloperidol are reversible processes, and after timely discontinuation, the blood system and blood vessels can return to normal
.
By transcriptome analysis of pluripotent hematopoietic stem/progenitor cells (Lin-Sca1+c-Kit+, LSK cells), haloperidol causes VEGF-A in LSK cells Decreased expression of isovascular growth factors is a possible mechanism
of vascular malformations.
The combined injection of haloperidol with VEGF-A can rescue bone marrow and liver vascular malformations
caused by haloperidol.
Haloperidol is one of the most commonly used and representative antipsychotics [7].
The authors found that short-term acute injection of haloperidol in mice caused significant dilation of blood vessels in hematopoietic organs such as bone marrow, liver, and spleen, but had no effect on blood vessels in non-hematopoietic organs such as brain and skin (Figure 1).
At the same time, the authors used the same treatment of mice with both antipsychotics Clozapine and chlorpromazine (Chlorpromazine) and obtained similar results
.
This demonstrates that antipsychotics can cause vascular malformations in hematopoietic organs without such effects
on non-hematopoietic organs.
1 Vasodilation of hematopoietic organs caused by antipsychotics (Source: Deng ZH, et al.
, FASEB J.
2022).
The authors performed a flow cytometry analysis of multi-organ blood cells from haloperidol-treated mice and detected Lin-c-Kit+ (LK) cells and common lymphoid progenitor cells CLP) and common myeloid progenitor cells (CMP) were significantly reduced, and the percentage of mature blood cells in the bone marrow, spleen, liver, and peripheral blood was disturbed These findings suggest that haloperidol disrupts hematopoietic stem and progenitor cells and interferes with hematopoietic function (Figure 2).
Fig.
2 Haloperidol disrupts hematopoiesis
(Source: Deng ZH, et al.
, FASEB J.
2022).
And, the authors found that the effects of drugs such as haloperidol on hematopoiesis and blood vessels are reversible processes (Figure 3).
After acute administration, blood cell disorders and vascular malformations caused by haloperidol can be restored, suggesting that timely monitoring of the number of blood cells and medication adjustment in the clinical application of the drug will avoid serious side effects
.
Fig.
3 Blood cell disorders and vascular malformations caused by haloperidol are reversible after discontinuation of the drug
(Source: Deng ZH, et al.
, FASEB J.
2022).
RNA sequencing analysis showed that vascular endothelial growth factor-A (VEGF-A) was a regulator of haloperidol in hematopoietic stem progenitor cells
.
In order to explore the relationship between the two, the authors injected VEGF-A in combination with haloperidol into mice, and found that vascular malformations in hematopoietic organs were greatly improved, indicating that haloperidol regulates the morphology of blood vessels in hematopoietic organs such as bone marrow through VEGF-A (Fig 4）
。
Fig.
4 VEGF-A rescues vasodilation caused by haloperidol
(Source: Deng ZH, et al.
, FASEB J.
2022).
Further, the authors found that haloperidol also hinders the regeneration
of blood vessels and blood during hematopoietic stem cell transplantation.
In the transplant regeneration model, vasodilation occurred in the haloperidol-treated mouse group, the mouse group knocked out the VEGF-A receptor in the vascular endothelium, and the blood cell knockout VEGF-A mouse group, while VEGF-A protein injection helped restore the vascular morphology (Figure 5).
5 VEGFA signaling regulates vascular recovery after bone marrow transplantation (Source: Deng ZH, et al.
, FASEB J.
2022).
Fig.
6 Haloperidol inhibits the release of VEGF-A from hematopoietic stem/progenitor cells and affects the vascular microenvironment
(Source: Deng ZH, et al.
, FASEB J.
2022).
Professor Liu Yang's previous published work proved that hematopoietic stem cells have the function of feedback regulation of vascular endothelium [8], which is crucial for hematological system remodeling, and found that the important neurotransmitter dopamine directly regulates the homeostasis maintenance and regeneration of hematopoietic stem cells through type 2 receptors[9]
。 In this study, we studied the blood and vascular changes caused by antipsychotic drugs targeting dopamine type 2 receptors, such as haloperidol, and linked dopamine receptors-HSPC-vascular endothelium, revealing that dopamine receptors regulate VEGF-A in HSPC Signal, feedback regulates the role of vascular endothelium (Figure 6).
This work further confirmed that the bidirectional interaction of hematopoietic stem progenitor cells and the microenvironment is of great
significance for the regulation of bone marrow homeostasis maintenance and regeneration.
Leukopenia caused by antipsychotics has been clinically reported, but the mechanism remains unclear [10].
This work provides a theoretical explanation
for this clinical phenomenon through laboratory animal studies.
This study suggests that timely blood cell monitoring during the use of antipsychotic drugs and avoiding the combination of hematopoietic stem cell transplantation and antipsychotic drugs will help avoid vascular and blood side effects
caused by such drugs.
The findings of this work also raise new questions to be studied, for example, whether HSPC may modulate vascular endothelium through feedback from factors other than VEGF-A.
In addition to causing abnormalities such as vasodilation of hematopoietic organs, what are the specific effects and related mechanisms of antipsychotic drugs on the function of vascular microenvironment? These questions will be answered
gradually in future work.
Original link:https://faseb.
onlinelibrary.
wiley.
com/doi/10.
1096/fj.
202200862R
The work was completed
by the School of Medicine of South China University of Technology, the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences, and the Max Planck Institute of Molecular Biomedical Research in Germany.
Deng Zhaohua and Zhong Jing from Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, and Jiang Hailin from South China University of Technology are the co-first authors of the paper, Professor Liu Yang from the School of Medicine of South China University of Technology and Guangzhou Biomedical Health Institute Professor Chen Qi is the co-corresponding author
of the paper.
The work was helped
by Prof.
Ralf Adams and Dr.
Hyun-woo Jeong of the Max Planck Institute of Molecular Biomedicine in Germany.
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End of this article
