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Characterization of the polymorphonuclear leukocyte-induced vasoconstriction in isolated human umbilical veins
1Department of Immunological Diseases, Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
Abstract:
We investigated the contractile effects of both activated and unactivated polymorphonuclear leukocytes (PMNs) on human vascular tissue to characterize the influence of human PMNs on vascular tone. PMNs were added either unactivated or after f-met-leu-phe (fMLP) activation (10(-8) M), into tissue chambers containing human umbilical vein segments under either control or cytokine-treated conditions. The activation state of different PMN preparations was measured by immunofluorescence staining of the adhesion glycoproteins Mac-1 and L-selectin. Both unactivated and activated PMNs induced a cell number-dependent (1.5 x 10(5) to 2 x 10(6) cells/ml) vasoconstriction in human umbilical vein segments. This PMN-induced response was not inhibited by treatment with indomethacin (10(-5) M), superoxide dismutase (2 x 10(-7) M) or L-nitro-monomethyl arginine (10(-4) M). However, treatment of PMNs with the leukotriene biosynthesis inhibitor BIRM-270 partially inhibited (-61 +/- 19%, P <.05) the contraction induced only by unactivated PMNs. Moreover, the supernatant from unactivated, but not that from activated, PMNs elicited a contractile response comparable to that from the addition of cells. We observed a significant correlation between the Mac-1/L-selectin ratio of activated PMNs and the contractile response they generated (r = 0.77, P <.05). The activated PMN response had an endothelium-dependent component, whereas the unactivated PMN response was endothelium-independent. These results suggest that human PMNs of varying activation states have the capacity to modulate vascular smooth muscle tone via distinct mechanisms. Unactivated PMNs appear to modulate tone via a secreted product, whereas the more activated phenotype modulates vascular tone via a cognate interaction with the endothelium.
Insights
Human polymorphonuclear leukocytes (PMNs) influence vascular tone through distinct mechanisms. Unactivated PMNs release products affecting smooth muscle, while activated PMNs interact with the endothelium, causing vasoconstriction.
Area of Science:
- Cardiovascular Biology
- Immunology
- Vascular Physiology
Background:
- Polymorphonuclear leukocytes (PMNs) are key immune cells involved in inflammation.
- The precise mechanisms by which PMNs modulate vascular tone remain incompletely understood.
Purpose of the Study:
- To investigate the contractile effects of activated and unactivated human PMNs on human vascular tissue.
- To characterize the distinct mechanisms underlying PMN-induced modulation of vascular tone.
Main Methods:
- Human umbilical vein segments were exposed to varying concentrations of unactivated or fMLP-activated human PMNs.
- PMN activation state was assessed via immunofluorescence staining for Mac-1 and L-selectin.
- Vascular responses were measured in the presence or absence of inhibitors and with or without functional endothelium.
Main Results:
- Both activated and unactivated PMNs induced concentration-dependent vasoconstriction in human umbilical vein segments.
- The vasoconstriction induced by unactivated PMNs was partially inhibited by a leukotriene biosynthesis inhibitor and was endothelium-independent.
- Activated PMN-induced vasoconstriction involved an endothelium-dependent component, with a correlation observed between the Mac-1/L-selectin ratio and contractile response.
Conclusions:
- Human PMNs, regardless of activation state, can modulate vascular tone.
- Unactivated PMNs exert effects via secreted products, whereas activated PMNs interact directly with the vascular endothelium.