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Methamphetamine-Induced Loss of Syndecan-1 and Retinal Endothelial Integrity via the TAAR-1/MMP-9 Pathway
Minsup Lee1, Taekyung Ha1, Ivan A Alvarez2,3
1Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA.
Background/Objectives:
Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood-brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries.
Methods:
We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors.
Results:
METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance.
Conclusions:
Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1-mediated MMP-9 upregulation. Targeting the TAAR-1/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina.
Insights
Methamphetamine (METH) damages retinal blood vessels by decreasing syndecan-1 and increasing MMP-9 via TAAR-1. Targeting this pathway may prevent METH-induced microvascular damage.
Area of Science:
- Ophthalmology
- Vascular Biology
- Pharmacology
Background:
- Methamphetamine (METH) is a psychostimulant known to harm the vascular system.
- While METH's effects on the blood-brain barrier are studied, its impact on retinal microvasculature is less understood.
- This study focuses on METH's effects on retinal microvascular endothelial cells and ophthalmic arteries.
Purpose of the Study:
- To investigate the effects of METH on syndecan-1 expression and endothelial function in rat retinal microvasculature.
- To explore the role of matrix metalloproteinase-9 (MMP-9) and trace amine-associated receptor 1 (TAAR-1) in METH-induced retinal vascular changes.
Main Methods:
- Assessed METH-induced changes in syndecan-1, MMP-2, and MMP-9 mRNA and protein levels.
- Evaluated endothelial function using scratch migration assays and trans-endothelial electrical resistance (TEER).
- Examined the mechanistic involvement of MMP-9 and TAAR-1 using pharmacological inhibitors.
Main Results:
- METH exposure decreased syndecan-1 and increased MMP-9 levels in retinal microvascular endothelial cells and ophthalmic arteries.
- Endothelial migration and barrier integrity (TEER) were impaired by METH.
- Inhibition of MMPs and TAAR-1 antagonism restored syndecan-1 expression and improved endothelial function.
Conclusions:
- METH induces retinal vascular damage by promoting TAAR-1-mediated MMP-9 upregulation, leading to syndecan-1 loss.
- Targeting the TAAR-1/MMP-9 pathway presents a potential therapeutic strategy for METH-induced retinal microvascular injury.
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