Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis.Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation.Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor.Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

IL-17A Contributes to the Angiotensin II-induced Neurovascular Coupling impairment through Oxidative Stress

Hypertension, a multifactorial chronic inflammatory condition, is a risk factor for neurodegenerative diseases including stroke and Alzheimer’s disease. These diseases have been associated with higher concentration of blood interleukin (IL)-17A. However, the role that IL-17A plays in the relationship between hypertension and brain remains misunderstood. Cerebral blood flow regulation may be the crossroads of these conditions. Hypertension alters cerebral blood flow regulation including neurovascular coupling (NVC). In the present study, the effects of IL-17A on NVC in the context of hypertension induced by angiotensin (Ang) II will be examined. Our results show that the neutralization of IL-17A or the specific inhibition of its receptor prevent the Ang II- induced NVC impairment. These treatments reduce the Ang II-induced cerebral oxidative stress. Tempol and NOX-2 depletion prevent NVC impairment induced by IL-17A. These findings suggest that IL-17A, through superoxide anion production, is an important mediator of cerebrovascular dysregulation induced by Ang II.

Cerebral hemodynamics: a mathematical model including autoregulation, baroreflex and extracranial peripheral circulation

Increasing evidence supports that cerebral autoregulation and mean arterial pressure regulation via baroreflex contribute to cerebral blood flow regulation. It is unclear whether the extracranial vascular bed of the head and neck helps reestablishing cerebral blood flow during changes in mean arterial pressure. Current computational models of cerebral blood flow regulation do not address the relationships between the intracranial and extracranial blood flow dynamics. We present a model of cerebral autoregulation, extracranial peripheral circulation and baroreflex control of heart rate and of peripheral vasculature that was included to the model of intracranial dynamics proposed by Linninger et al. (2009), which incorporates the fully coupled blood, cerebrospinal fluid and brain parenchyma systems. Autoregulation was modelled as being pressure-mediated at the arteries and arterioles and flow-mediated at the microcirculation. During simulations of a bout of acute hypotension, cerebral blood flow returns rapidly to baseline levels with a very small overshoot, whereas the blood flow to the peripheral circulation of the head and neck suffers a prolonged suppression in accordance with experimental evidence. The inclusion of baroreflex regulation at the extracranial vascular bed had a negligible effect on cerebral blood flow regulation during dynamic changes in mean arterial pressure. Moreover, the results suggest that the extracranial blood flow carries only modest information about cerebral blood flow in dynamic situations in which cerebral autoregulation is preserved and mean arterial pressure suffers alterations. This information is likely higher when the autoregulation is impaired. Steady-state cerebral blood flow in the model is kept within normal ranges despite variations in mean arterial pressure from 50 to 175 mmHg. By inputting aortic pressure waves from individuals with increasing arterial rigidity, increasing arterial systolic and pulse pressures, the model predicts the generation of intracranial pressure waves with accordingly increasing peaks and amplitudes.

Perivascular Macrophages Regulate Blood Flow Following Tissue Damage

Rationale: Ischemic injuries remain a leading cause of mortality and morbidity worldwide, and restoration of functional blood perfusion is vital to limit tissue damage and support healing. Objective: To reveal a novel role of macrophages in reestablishment of functional tissue perfusion following ischemic injury that can be targeted to improve tissue restoration. Methods and Results: Using intravital microscopy of ischemic hind limb muscle in mice, and confocal microscopy of human tissues from amputated legs, we found that macrophages accumulated perivascularly in ischemic muscles, where they expressed high levels of iNOS. Genetic depletion of iNOS specifically in macrophages (Cx3cr1-CreERT2;Nos2fl/fl or LysM-Cre;Nos2fl/fl) did not affect vascular architecture but highly compromised blood flow regulation in ischemic but not healthy muscle, which resulted in aggravated ischemic damage. Thus, the ability to upregulate blood flow was shifted from eNOS (endothelial)-dependence in healthy muscles to completely rely on macrophage-derived iNOS during ischemia. Macrophages in ischemic muscles expressed high levels of CXCR4 and CCR2, and local overexpression by DNA plasmids encoding the corresponding chemokines CXCL12 or CCL2 increased macrophage numbers, while CXCL12 but not CCL2 induced their perivascular positioning. As a result, CXCL12-overexpression increased the number of perfused blood vessels in the ischemic muscles, improved functional muscle perfusion in a macrophage-iNOS-dependent manner, and ultimately restored limb function. Conclusions: This study establishes a new function for macrophages during tissue repair, as they regulate blood flow through the release of iNOS-produced NO. Further, we demonstrate that macrophages can be therapeutically targeted to improve blood flow regulation and functional recovery of ischemic tissues.