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Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies.

Jimenez-Andrade JM, Herrera MB, Ghilardi JR, Vardanyan M, Melemedjian OK, Mantyh PW - Mol Pain (2008)

Bottom Line: This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG.Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy.Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA. jmjimene@email.arizona.edu

ABSTRACT
Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

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Whole mount preparation showing the vascularization of the cell body rich area of the dorsal root ganglia (DRG) vs. the dorsal and ventral roots and sciatic nerve at L4 in the C3H mouse. Bright-field photomicrograph of a whole-mount L4 DRG preparation for anatomical reference. Dashed line demarks the cell body-rich area from the sciatic nerve and dorsal and ventral spinal roots (A). Representative confocal micrograph of a mouse L4 DRG labeled with the endothelial cell marker CD31 showing the marked difference in the density of the vascular supply within the sensory ganglia as compared to the corresponding spinal nerve and dorsal root (B). This dense vascularization of the DRG along with the large fenestrations of the blood vessels in the DRG may partially explain why certain neurotoxics preferential accumulate in the DRG and produce a primarily sensory vs. motor neuropathy. The confocal image in (B) was assembled from 280 optical sections acquired at 0.5 μm z-plane intervals so that the total z stack is 140 μm-thick. Scale bar = 100 μm.
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Figure 1: Whole mount preparation showing the vascularization of the cell body rich area of the dorsal root ganglia (DRG) vs. the dorsal and ventral roots and sciatic nerve at L4 in the C3H mouse. Bright-field photomicrograph of a whole-mount L4 DRG preparation for anatomical reference. Dashed line demarks the cell body-rich area from the sciatic nerve and dorsal and ventral spinal roots (A). Representative confocal micrograph of a mouse L4 DRG labeled with the endothelial cell marker CD31 showing the marked difference in the density of the vascular supply within the sensory ganglia as compared to the corresponding spinal nerve and dorsal root (B). This dense vascularization of the DRG along with the large fenestrations of the blood vessels in the DRG may partially explain why certain neurotoxics preferential accumulate in the DRG and produce a primarily sensory vs. motor neuropathy. The confocal image in (B) was assembled from 280 optical sections acquired at 0.5 μm z-plane intervals so that the total z stack is 140 μm-thick. Scale bar = 100 μm.

Mentions: Whole mount lumbar DRG with adjacent roots and spinal nerve attached were isolated from C3H/HeJ mice. While CD31+ blood vessels were present only sparsely within the endoneurium of the sciatic nerve, a dense network of CD31+ blood vessels was observed within the L4 DRG (Figure 1). In order to elucidate the association of blood vessels with cell bodies and axons of the sensory neurons within the DRG, CD31 immunohistochemical analysis on whole-mount preparations was conducted in L4 DRG of transgenic C57/B6 mice which constitutively express yellow fluorescence protein (YFP) in axons and cell bodies of sensory neurons (Fig 2A) [28,29]. YFP immunofluorescence was readily visible in cell bodies and axons of sensory neurons without signal amplification (Fig 2A). The 3D reconstructions of the confocal scans show the cell body-rich area (CBRA) is vascularized by an extensive network of CD31+ blood vessels that encapsulate and encircle the cell body of the YFP-expressing sensory neurons (Fig 2B,C). In contrast, the nerve fiber-rich area (NFRA) of the DRG contains relatively few CD31+ blood vessels (Fig 2B,D), and when present, run parallel to the bundles of nerve fibers.


Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies.

Jimenez-Andrade JM, Herrera MB, Ghilardi JR, Vardanyan M, Melemedjian OK, Mantyh PW - Mol Pain (2008)

Whole mount preparation showing the vascularization of the cell body rich area of the dorsal root ganglia (DRG) vs. the dorsal and ventral roots and sciatic nerve at L4 in the C3H mouse. Bright-field photomicrograph of a whole-mount L4 DRG preparation for anatomical reference. Dashed line demarks the cell body-rich area from the sciatic nerve and dorsal and ventral spinal roots (A). Representative confocal micrograph of a mouse L4 DRG labeled with the endothelial cell marker CD31 showing the marked difference in the density of the vascular supply within the sensory ganglia as compared to the corresponding spinal nerve and dorsal root (B). This dense vascularization of the DRG along with the large fenestrations of the blood vessels in the DRG may partially explain why certain neurotoxics preferential accumulate in the DRG and produce a primarily sensory vs. motor neuropathy. The confocal image in (B) was assembled from 280 optical sections acquired at 0.5 μm z-plane intervals so that the total z stack is 140 μm-thick. Scale bar = 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2289805&req=5

Figure 1: Whole mount preparation showing the vascularization of the cell body rich area of the dorsal root ganglia (DRG) vs. the dorsal and ventral roots and sciatic nerve at L4 in the C3H mouse. Bright-field photomicrograph of a whole-mount L4 DRG preparation for anatomical reference. Dashed line demarks the cell body-rich area from the sciatic nerve and dorsal and ventral spinal roots (A). Representative confocal micrograph of a mouse L4 DRG labeled with the endothelial cell marker CD31 showing the marked difference in the density of the vascular supply within the sensory ganglia as compared to the corresponding spinal nerve and dorsal root (B). This dense vascularization of the DRG along with the large fenestrations of the blood vessels in the DRG may partially explain why certain neurotoxics preferential accumulate in the DRG and produce a primarily sensory vs. motor neuropathy. The confocal image in (B) was assembled from 280 optical sections acquired at 0.5 μm z-plane intervals so that the total z stack is 140 μm-thick. Scale bar = 100 μm.
Mentions: Whole mount lumbar DRG with adjacent roots and spinal nerve attached were isolated from C3H/HeJ mice. While CD31+ blood vessels were present only sparsely within the endoneurium of the sciatic nerve, a dense network of CD31+ blood vessels was observed within the L4 DRG (Figure 1). In order to elucidate the association of blood vessels with cell bodies and axons of the sensory neurons within the DRG, CD31 immunohistochemical analysis on whole-mount preparations was conducted in L4 DRG of transgenic C57/B6 mice which constitutively express yellow fluorescence protein (YFP) in axons and cell bodies of sensory neurons (Fig 2A) [28,29]. YFP immunofluorescence was readily visible in cell bodies and axons of sensory neurons without signal amplification (Fig 2A). The 3D reconstructions of the confocal scans show the cell body-rich area (CBRA) is vascularized by an extensive network of CD31+ blood vessels that encapsulate and encircle the cell body of the YFP-expressing sensory neurons (Fig 2B,C). In contrast, the nerve fiber-rich area (NFRA) of the DRG contains relatively few CD31+ blood vessels (Fig 2B,D), and when present, run parallel to the bundles of nerve fibers.

Bottom Line: This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG.Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy.Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA. jmjimene@email.arizona.edu

ABSTRACT
Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or the distal or proximal aspect of the sciatic nerve. This dense vascularization, coupled with the high permeability of these capillaries, may synergistically contribute, and in part explain, why many potentially neurotoxic agents preferentially accumulate and injure cells within the DRG. Currently, cancer survivors and HIV patients constitute the largest and most rapidly expanding groups that have chemically induced peripheral sensory neuropathy. Understanding the unique aspects of the vascularization of the DRG and closing the endothelial fenestrations of the rich vascular bed of capillaries that vascularize the DRG before intravenous administration of anti-neoplastic or anti-HIV therapies, may offer a mechanism based approach to attenuate these chemically induced peripheral neuropathies in these patients.

Show MeSH
Related in: MedlinePlus