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.

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Altered blood flow regulation in autotransplanted pancreatic islets of rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.259.1.e52 ◽

1990 ◽

Vol 259 (1) ◽

pp. E52-E56 ◽

Cited By ~ 4

Author(s):

L. Jansson ◽

S. Sandler

Keyword(s):

Blood Flow ◽

Pancreatic Islets ◽

Blood Perfusion ◽

Flow Regulation ◽

Adult Rats ◽

Partial Pancreatectomy ◽

Pancreatic Remnant ◽

Islet Blood Flow ◽

Blood Flow Regulation ◽

Other Substances

Adult rats were partially depancreatized, and approximately 500 islets were isolated from each excised pancreas, maintained in tissue culture for 7 days, and subsequently transplanted back to the same animals beneath the renal capsule. Four weeks after transplantation the animals were anesthetized and given an intravenous injection of 1 ml of either saline, 30% (wt/vol) D-glucose, 30% (wt/vol) D-galactose, DL-propranolol (15 mg/kg body wt) dissolved in saline, or terbutaline (1 mg/kg body wt) dissolved in saline. Five minutes later blood perfusion of the islet grafts and the pancreatic remnant were measured with a microsphere technique. Islet blood flow was also measured in animals with pancreas intact and no islet grafts after administration of saline, glucose, or galactose. These animals demonstrated a significant and preferential increase in islet blood flow after glucose administration, whereas galactose caused a selective decrease in islet blood perfusion. Both whole pancreatic blood flow and islet blood flow in the pancreatic remnant were decreased by terbutaline administration, whereas the other substances had no effect. Blood flow to the transplanted islets was decreased by glucose and galactose, whereas propranolol and terbutaline had no effect compared with the saline-injected animals. These results suggest that blood flow regulation differs between transplanted pancreatic islets, islets in the normal pancreas, and islets in the pancreatic remnant after partial pancreatectomy. Whether this reflects lack of innervation or an altered reactivity of the newly formed blood vessels in islet grafts is presently unknown.

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Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.2.g454 ◽

2000 ◽

Vol 279 (2) ◽

pp. G454-G462 ◽

Cited By ~ 82

Author(s):

Sven Richter ◽

Isabella Mücke ◽

Michael D. Menger ◽

Brigitte Vollmar

Keyword(s):

Blood Flow ◽

Venous Blood ◽

Blood Perfusion ◽

Flow Regulation ◽

Arterial Blood Flow ◽

Venous Blood Flow ◽

Total Blood ◽

Arterial Blood ◽

Blood Flow Regulation ◽

The Impact

The hepatic arterial buffer response (HABR) effectively controls total blood perfusion in normal livers, but little is known about blood flow regulation in cirrhosis. We therefore studied the impact of HABR on blood perfusion of cirrhotic livers in vivo. After 8-wk CCl4 treatment to induce cirrhosis, 18 anesthetized rats (and 18 noncirrhotic controls) were used to simultaneously assess portal venous and hepatic arterial inflow with miniaturized ultrasonic flow probes. Stepwise hepatic arterial blood flow (HAF) or portal venous blood flow (PVF) reduction was performed. Cirrhotic livers revealed a significantly reduced total hepatic blood flow (12.3 ± 0.9 ml/min) due to markedly diminished PVF (7.3 ± 0.8 ml/min) but slightly increased HAF (5.0 ± 0.6 ml/min) compared with noncirrhotic controls (19.0 ± 1.6, 15.2 ± 1.3, and 3.8 ± 0.4 ml/min). PVF reduction caused a significant HABR, i.e., increase of HAF, in both normal and cirrhotic livers; however, buffer capacity of cirrhotic livers exceeded that of normal livers ( P < 0.05) by 1.7- to 4.5-fold (PVF 80% and 20% of baseline). Persistent PVF reduction for 1, 2, and 6 h demonstrated constant HABR in both groups. Furthermore, HABR could be repetitively provoked, as analyzed by intermittent PVF reduction. HAF reduction did not induce changes of portal flow in either group. Because PVF is reduced in cirrhosis, the maintenance of HAF and the preserved HABR must be considered as a protective effect on overall hepatic circulation, counteracting impaired nutritive blood supply via the portal vein.

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