Significance: The human circulatory system includes the heart, arteries, veins, and capillaries, all of which are lined by endothelial cells to prevent the escape of vascular contents into surrounding tissues. Platelets are blood cells that are best known for their essential role in preventing blood loss after injury. Here, we employed sensitive methods to measure changes in vascular barrier function in vivo and used them to identify a role for platelets in maintaining vascular homeostasis. The results highlight the role of platelet collagen receptors and dense granules, show which vessels are particularly dependent on platelets for this purpose, and point to an underappreciated interchange between platelets and endothelial cells that is lost in severe thrombocytopenia.

At present, the worldwide prevalence of obesity has become alarmingly high with estimates foreshadowing a continued escalation in the future. Furthermore, there is growing evidence attributing an individual’s predisposition for developing obesity to maternal health during gestation. Currently, 60% of pregnancies in the US are to either overweight or obese mothers which in turn contributes to the persistent rise in obesity rates. While obesity itself is problematic, it conveys an increased risk for several diseases such as diabetes, inflammatory disorders, cancer and cardiovascular disease (CVD). Additionally, as we are learning more about the mechanisms underlying CVD, much attention has been brought to the role of perivascular adipose tissue (PVAT) in maintaining cardiovascular health. PVAT regulates vascular tone and for a significant number of individuals, obesity elicits PVAT disruption and dysregulation of vascular function. Obesity elicits changes in adipocyte and leukocyte populations within PVAT leading to an inflammatory state which promotes vasoconstriction thereby aiding the onset/progression of CVD. Our current understanding of obesity, PVAT and CVD has only been examined at the individual level without consideration for a maternal programming effect. It is unknown if maternal obesity affects the propensity for PVAT remodeling in the offspring, thereby enhancing the obesity/CVD link, and what role PVAT leukocytes play in this process. This perspective will focus on the maternal contribution of the interplay between obesity, PVAT disruption and CVD and will highlight the leukocyte/PVAT interaction as a novel target to stem the tide of the current obesity epidemic and its secondary health consequences.

Perivascular adipose tissue (PVAT) regulates vascular tone and is composed of adipocytes and several leukocyte subpopulations. Diet can modify PVAT function, as obesogenic diets cause morphological changes to adipocytes and skew the leukocyte phenotype, leading to PVAT dysregulation and impaired vasoregulation. Of note, platelets, the clot-forming cells, also modulate many facets of leukocyte activity, such as tissue infiltration and polarity. We aimed to determine whether platelets regulate the leukocyte populations residing within PVAT. Male C57Bl/6J mice were fed a Western diet (30% kcal sucrose, 40% kcal fat, 8.0% sodium) to develop obesogenic conditions for PVAT leukocyte remodeling. Diet was either administered acutely (2 weeks) or extended (8 weeks) to gauge the length of challenge necessary for remodeling. Additionally, platelet depletion allowed for the assessment of platelet relevance in PVAT leukocyte remodeling. Abdominal PVAT (aPVAT) and thoracic PVAT (tPVAT) were then isolated and leukocyte composition evaluated by flow cytometry. Compared to control, Western diet alone did not significantly impact PVAT leukocyte composition for either diet length. Platelet depletion, independent of diet, significantly disrupted PVAT leukocyte content with monocytes/macrophages most impacted. Furthermore, tPVAT appeared more sensitive to platelet depletion than aPVAT, providing novel evidence of platelet regulation of leukocyte composition within PVAT depots.

Platelets are responsible for maintaining vascular integrity through the process of hemostasis with glycoprotein VI (GPVI) acting as a major receptor for platelet activation. Interestingly, platelet participation in inflammation is an evolving concept with few studies exploring GPVI in the framework of inflammation and even less in the context of the most severe inflammatory condition: sepsis. Here we utilized a GPVI deficient mouse model (GPVI ^−/− ) to elucidate the role of GPVI in the formation of circulating platelet‐leukocyte aggregates (PLAs) and how GPVI driven modifications impact leukocyte phenotype and function under septic systemic inflammatory conditions. Using the cecal ligation and puncture (CLP) technique to model sepsis in male mice, we report GPVI‐mediated modification of several inflammatory characteristics. GPVI deficiency reduced platelet adhesion to neutrophils and monocytes during sepsis, resulting in reduced neutrophil and increased monocyte activation. Furthermore, monocytes exhibited altered polarization with GPVI deletion, raising the levels of circulating non‐classical monocytes. The loss of GPVI also elicited a significant reduction in the levels of circulating TNFα. Finally, sepsis‐induced mortality was significantly exacerbated as survival was dramatically reduced in GPVI ^−/− mice over a five‐day period. These findings suggest that platelet GPVI impacts the inflammatory response during sepsis in a previously undocumented manner.