In vivo imaging of cerebral microvascular plasticity from birth to death. J Cereb Blood Flow Metab

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism (Impact Factor: 5.41). 10/2012; 33(1). DOI: 10.1038/jcbfm.2012.152
Source: PubMed


Cerebral function and viability are critically dependent on efficient delivery of oxygen and glucose through the microvasculature. Here, we studied individual microvessels in the intact brain using high-resolution confocal imaging and long-term time-lapse two-photon microscopy across the lifetime of a mouse. In the first postnatal month, we found large-scale sprouting but to our surprise the majority of sprouts underwent pruning and only a small fraction became perfused capillaries. After the first month, microvessel formation and elimination decreased and the net number of vessels stabilized. Although vascular stability was the hallmark of the adult brain, some vessel formation and elimination continued throughout life. In young adult mice, vessel formation was markedly increased after exposure to hypoxia; however, upon return to normoxia, no vessel elimination was observed, suggesting that new vessels constitute a long-term adaptive response to metabolic challenges. This plasticity was markedly reduced in older adults and aging where hypoxia-induced angiogenesis was absent. Our study describes, for the first time in vivo patterns of cerebral microvascular remodeling throughout life. Disruption of the observed balance between baseline turnover and vascular stability may underlie a variety of developmental and age-related degenerative neurological disorders.Journal of Cerebral Blood Flow & Metabolism advance online publication, 24 October 2012; doi:10.1038/jcbfm.2012.152.

Download full-text


Available from: Jaime Grutzendler, Feb 21, 2015
1 Follower
44 Reads
  • Source
    • "Of all the organs, the brain has the most intensive metabolic activity. The young adult brain retains the ability to form vessels under hypoxic conditions, but this capacity is lost in mature and aged brains (Shao et al., 2010; Sonnotag et al., 1997; Harb et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Brain microcirculation plays an important role in the pathogenesis of various brain diseases. Several specific features of the circulation in the brain and its functions deserve special attention. The brain is extremely sensitive to hypoxia, and brain edema is more dangerous than edema in other tissues. Brain vessels are part of the blood-brain barrier, which prevents the penetration of some of the substances in the blood into the brain tissue. Herein, we review the processes of angiogenesis and the changes that occur in the brain microcirculation in the most prevalent neurodegenerative diseases. There are no uniform vascular changes in the neurodegenerative diseases. In some cases, the vascular changes are secondary consequences of the pathological process, but they could also be involved in the pathogenesis of the primary disease and contribute to the degeneration of neurons, based on their quantitative characteristics. Additionally, we described the stereological methods that are most commonly used for generating qualitative and quantitative data to assess changes in the microvascular bed of the brain.
    Reviews in the neurosciences 10/2014; 26(1). DOI:10.1515/revneuro-2014-0049 · 3.33 Impact Factor
  • Source
    • "Both these results were reported (see Fig. 4, Keller et al. 2011). Much of the brain's vascular system forms during fetal life, but considerable elaboration and remodeling of vessels occur during postnatal life (Harb et al. 2013). In the macaque, CO Figure 8. Differences between layer 2 and layer 3 can affect measurement of blood vessel density and size. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The vascular supply to layers and columns was compared in macaque primary visual cortex (V1) by labeling red blood cells via their endogenous peroxidase activity. Alternate sections were processed for cytochrome oxidase to reveal “patches” or “blobs,” which anchor the interdigitated column systems of striate cortex. More densely populated cell layers received the most profuse blood supply. In the superficial layers the blood supply was organized into microvascular lobules, consisting of a central venule surrounded by arterioles. Each vessel was identified as an arteriole or venule by matching it with the penetration site where it entered the cortex from a parent arteriole or venule in the pial circulation. Although microvascular lobules and cytochrome oxidase patches had a similar periodicity, they bore no mutual relationship. The size and density of penetrating arterioles and venules did not differ between patches and interpatches. The red blood cell labeling in patches and interpatches was equal. Moreover, patches and interpatches were supplied by an anastomotic pial arteriole system, with no segregation of blood supply to the two compartments. Often a focal constriction was present at the origin of pial arterial branches, indicating that local control of cortical perfusion may be accomplished by vascular sphincters.
    Cerebral Cortex 09/2014; DOI:10.1093/cercor/bhu221 · 8.67 Impact Factor
  • Source
    • "The latter concept is supported by the following findings: (1) VEGFR2 gene expression decreases with development (Greene et al., 2011). Also, vessel branching in the brain increases until 10 days postpartum and stabilizes to adult levels between days 10 and 25 in mice (Harb et al., 2013); (2) mature (4–5 month old) mouse brains lose their ability to undergo angiogenesis in response to hypoxia (Harb et al., 2013), suggesting that the process of angiogenesis , even in stressful conditions, is limited after birth; (3) VEGF production and activity are both impaired in the feto-placental circulation during preeclampsia (Lyall et al., 1997; Andraweera et al., 2012; Kim et al., 2012); (4) Inhibition of angiogenesis with humanized antibodies targeting VEGF or orally active small tyrosine kinase inhibitors targeting VEGF receptors is commonly associated with severe hypertension (Lankhorst et al., 2013); (5) Loss of microvessel growth has been reported to precede elevations in blood pressure (Murfee and Schmid-Schonbein, 2008); (6) Programming of elevated blood pressure in the offspring has been associated with a reduced angiogenic capacity of vessels cultured in vitro (Pladys et al., 2005). Taking all these data into account, we believe that abnormal angiogenic processes present after birth in offspring born from preeclamptic pregnancies may contribute to elevation in blood pressure later in life. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.
    Frontiers in Pharmacology 06/2014; 5:134. DOI:10.3389/fphar.2014.00134 · 3.80 Impact Factor
Show more