RESUMO
After cardiac ischaemia, a prolonged decrease of coronary microvascular perfusion often occurs even after flow is restored in an upstream artery. This 'no-reflow' phenomenon worsens patient prognosis. In the brain, after stroke, a similar post-ischaemic 'no-reflow' has been attributed to capillary constriction by contractile pericytes. We now show that occlusion of a rat coronary artery, followed by reperfusion, blocks 40% of cardiac capillaries and halves perfused blood volume within the affected region. Capillary blockages colocalised strongly with pericytes, where capillary diameter was reduced by 37%. The pericyte relaxant adenosine increased capillary diameter by 21% at pericyte somata, decreased capillary block by 25% and increased perfusion volume by 57%. Thus, cardiac pericytes constrict coronary capillaries and reduce microvascular blood flow after ischaemia, despite re-opening of the culprit artery. Cardiac pericytes are therefore a novel therapeutic target in ischaemic heart disease.
Assuntos
Capilares/fisiopatologia , Vasos Coronários/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Pericitos/fisiologia , Animais , Perfusão , RatosRESUMO
Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.
Assuntos
Pericitos/fisiologia , Animais , Capilares/citologia , Capilares/fisiologia , Circulação Cerebrovascular/fisiologia , Humanos , Pericitos/ultraestrutura , Terminologia como AssuntoRESUMO
Despite efforts to restore tissue perfusion after myocardial infarction, coronary no-reflow--a failure to achieve adequate reperfusion of the cardiac microcirculation--is a common complication, which correlates with an increased incidence of death and disability. The treatment of ischaemic stroke is also plagued by no-reflow and, in the brain, a major cause of this phenomenon has been shown to be contractile microvascular pericytes irreversibly constricting capillaries and dying. We propose that cardiac pericytes, which are the second most-common cell type in the heart, impede reperfusion of coronary capillaries in a similar fashion to those in the brain after a stroke. Pericyte constriction might contribute to morbidity in patients by causing microvascular obstruction, even after successful treatment of coronary artery block. The similarity of the no-reflow phenomenon in the brain and in the heart suggests that cardiac pericytes are a novel therapeutic target for coronary no-reflow after myocardial infarction.
Assuntos
Circulação Coronária/fisiologia , Microcirculação/fisiologia , Infarto do Miocárdio/patologia , Pericitos/patologia , Humanos , Infarto do Miocárdio/fisiopatologiaRESUMO
Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.
Assuntos
Capilares/citologia , Circulação Cerebrovascular/fisiologia , Pericitos/fisiologia , Animais , Arteríolas/fisiologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Isquemia Encefálica/patologia , Capilares/efeitos dos fármacos , Morte Celular , Cerebelo/irrigação sanguínea , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/citologia , Circulação Cerebrovascular/efeitos dos fármacos , Dinoprostona/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Neuroimagem Funcional , Ácido Glutâmico/farmacologia , Ácidos Hidroxieicosatetraenoicos/biossíntese , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Pericitos/citologia , Pericitos/efeitos dos fármacos , Pericitos/patologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Glutamato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Vasoconstrição , Vasodilatação/efeitos dos fármacosRESUMO
The cerebral circulation is highly specialized, both structurally and functionally, and it provides a fine-tuned supply of oxygen and nutrients to active regions of the brain. Our understanding of blood flow regulation by cerebral arterioles has evolved rapidly. Recent work has opened new avenues in microvascular research; for example, it has been demonstrated that contractile pericytes found on capillary walls induce capillary diameter changes in response to neurotransmitters, suggesting that pericytes could have a role in neurovascular coupling. This concept is at odds with traditional models of brain blood flow regulation, which assume that only arterioles control cerebral blood flow. The investigation of mechanisms underlying neurovascular coupling at the capillary level requires a range of approaches, which involve unique technical challenges. Here we provide detailed protocols for the successful physiological and immunohistochemical study of pericytes and capillaries in brain slices and isolated retinae, allowing investigators to probe the role of capillaries in neurovascular coupling. This protocol can be completed within 6-8 h; however, immunohistochemical experiments may take 3-6 d.