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De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury
Open accessAbstract
The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4−/− mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.
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Citations
Cited by
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Stokum, J. A., Gerzanich, V., & Simard, J. M. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15617172 · Cited by 587
Self-citationAdvances in TRP channel drug discovery: from target validation to clinical studies
Koivisto, A.-P., Belvisi, M. G., Gaudet, R., & Szallasi, A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00268-4 · Cited by 537
Transient Receptor Potential Channels in the Vasculature
Earley, S., & Brayden, J. E. (2015) · Physiological Reviews · doi:10.1152/physrev.00026.2014 · Cited by 420
Chen, Z., Mao, X., Liu, A., Gao, X., Chen, X., Ye, M., Ye, J., Liu, P., Xu, S., Liu, J., et al. (2015) · Neurochemical Research · doi:10.1007/s11064-014-1483-z · Cited by 51
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Metadata
- Authors
- Gerzanich, V., Woo, S. K., Vennekens, R., Tsymbalyuk, O., Ivanova, S., Ivanov, A., Geng, Z., Chen, Z., Nilius, B., Flockerzi, V., Freichel, M., & Simard, J. M.
- Venue
- Nature Medicine
- Published
- 2009-01-25
- Volume
- 15
- Issue
- 2
- Pages
- 185-191
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1978669570
- Cited by
- 224
- References
- 0
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Gerzanich, V., Woo, S. K., Vennekens, R., Tsymbalyuk, O., Ivanova, S., Ivanov, A., Geng, Z., Chen, Z., Nilius, B., Flockerzi, V., Freichel, M., & Simard, J. M. (2009). De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nature Medicine. https://doi.org/10.1038/nm.1899
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