BackgroundEndothelial cell responses during inflammation are heterogeneous and key for selectivity in how leukocytes hone in on specific sites and why vascular diseases are highly bed specific. However, mechanisms for this specificity remain unclear.Methods and ResultsHere, we exposed human endothelial cells isolated from 5 systemic arterial beds from 1 donor (to overcome donor‐to‐donor genetic/epigenetic differences), the umbilical vein, and pulmonary microvasculature to TNF‐α, LPS, and IL‐1β and assessed acute (ERK1/2 and p65) and chronic (ICAM‐1, VCAM‐1 total and surface expression) signaling responses and assessed changes in surface N‐glycans and monocyte adhesion. Significant diversity in responses was evident by disparate changes in ERK1/2 and p65 NF‐κB phosphorylation, which varied up to 5‐fold between different cells and in temporal and magnitude differences in ICAM‐1 and VCAM‐1 expression (maximal VCAM‐1 induction typically being observed by 4 hours, whereas ICAM‐1 expression was increased further at 24 hours relative to 4 hours). N‐glycan profiles both basally and with stimulation were also bed specific, with hypoglycosylated N‐glycans correlating with increased THP‐1 monocyte adhesion. Differences in surface N‐glycan expression tracked with dynamic up‐ or downregulation of α‐mannosidase activity during inflammation.ConclusionsThese results demonstrate a critical role for the vascular bed of origin in controlling endothelial responses and function to inflammatory stimuli and suggest that bed‐specific expression of N‐linked sugars may provide a signature for select leukocyte recruitment.

Exposure to chlorine (Cl2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl2 gas exposure (400ppm, 30min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex-vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24–48 hours post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by ~2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (~4mmHg) lower in rats that had been exposed to Cl2 gas 24 hours earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl2 gas exposure toxicity.

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