Imaging the hemodynamics of pial collaterals and evaluating collateral therapeutics in rodent models of acute ischemic stroke

• Author / Creator

  Junqiang, Ma

• Ischemic stroke is caused by blockage of a primary blood vessel supplying brain tissue. Cerebral collaterals are auxiliary vascular pathways in the cerebral circulation that can provide residual blood flow to partially maintain perfusion in ischemic tissue when primary vascular routes are blocked. Thus, it is collateral blood flow that slows down the progression of ischemic penumbra to irreversible ischemic damage. In this thesis, we investigated hemodynamic evolution of pial collaterals after stroke and provide preclinical evidence for a pair of pial collateral enhancement treatments (RIPerC and intravenous milrinone administration) to facilitate bench to bedside translation. To evaluate collateral flow during cerebral ischemia, laser speckle contrast imaging (LSCI) and two photon laser scanning microscopy (TPLSM) were used to image pial collaterals between the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) in male Sprague Dawley rats during distal middle cerebral artery occlusion (dMCAo).

  Ischemic stroke is age related and disproportionately affects the elderly. Aging leads to rarefaction of cerebral vessels and thereby accelerates ischemic injury by reducing penumbral blood flow via collaterals. Dynamic changes in pial collaterals after onset of cerebral ischemia may vary with age but have not been extensively studied. Therefore, in Chapter 2 we tested the hypothesis that retrograde pial collateral flow would be recruited immediately after dMCAo in both aged and young rats, but that aging would accelerate collateral failure over time and lead to more severe ischemic damage. Our LSCI showed that cerebral collateral perfusion declined over time after stroke in aged and young rats, and that this decline was significantly greater in aged rats. TPLSM demonstrated that collateral failure is more severe in aged rats with significantly impaired pial collateral dynamics (reduced diameter, red blood cell velocity and red blood cell flux) relative to young adult rats. The accelerated collapse of pial collateral blood flow in aged rats exacerbated the insufficient perfusion of the penumbra and lead to greater ischemic damage than in young adult rats.

  The dropout of collaterals during stroke is related to the progression of penumbra to irreversible ischemic infarct and impaired response to treatment. Enhancing cerebral pial collateral blood flow may therefore reduce ischemic damage. Remote ischemic perconditioning (RIPerC) involves inducing peripheral ischemia (typically in the limbs) during stroke and may reduce brain damage due to cerebral ischemia. In Chapter 3, we hypothesized that RIPerC treatment would induce a significant increase in blood flow through pial collaterals by enhanced dilation of pial collaterals relative to control rats. Our data clearly demonstrated that RIPerC significantly reduced early ischemic damage measured 6 h after stroke onset in both aged and young rats. This neuroprotective effect of RIPerC occurred at least in part due to the prevention of pial collateral collapse. While control rats exhibited an initial dilation followed by a progressive narrowing of pial arterioles after stroke, such constriction was prevented or reversed by RIPerC. Given the impairment in collateral blood flow observed in aged rats in Chapter 2, in Chapter 4 we examined the ability of RIPerC to drive collateral flow in aged animals. Relative blood flow after dMCAO measured with LSCI suggested enhancement of blood flow in RIPerC treated aged stroke rats. Using TPLSM, we confirmed that RIPerC enhanced penumbral perfusion through pial collaterals and maintained retrograde blood flow from ACA to distal MCA segments. This improved flow was associated with reduced early ischemic damage in RIPerC treated aged rats.

  Milrinone is a potent selective phosphodiesterase 3 (PDE3) inhibitor that inhibits cAMP specific PDE3 in both cardiac myocytes and vascular smooth muscle cells. PDE3 inhibitors may therefore have a cerebral vasodilatory effect with concomitant augmentation of cardiac output. We hypothesized that systemic pharmacotherapy with milrinone lactate would be effective for augmenting pial collateral flow and reducing cerebral ischemic damage. Using LSCI, we found that milrinone increased collateral flow acutely. Moreover, continuous subacute administration of milrinone was well tolerated. However, no significant reduction in infarct volume was found after five days of treatment.

  In conclusion, the data herein demonstrates that aging has a detrimental effect on pial collateral flow during ischemic stroke. New therapeutic strategies aiming at modulating cerebral collateral flow, including RIPerC and milrinone, have translational potential as collateral therapeutics to reduce ischemic damage.  

• Subjects / Keywords

  • ischemic stroke
  • pial collaterals

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-a92k-h632

• License

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