The Vasculature within the Paraventricular Nucleus of the Hypothalamus in Mice Varies as a Function of Development, Subnuclear Location, and GABA Signaling

Abstract

The paraventricular nucleus of the hypothalamus (PVN) is a cell group that plays important roles in regulating sympathetic vasomotor tone, food intake, neuroendocrine and autonomic stress responses, and cardiovascular function. The developing PVN is surrounded by neuronal elements containing, and presumably secreting, gamma-aminobutyric acid (GABA). The vasculature of the adult PVN is notably denser than in other brain regions or in the PVN during perinatal development. To characterize the postnatal angiogenic process in mice, blood vessels were analyzed at P8, 20, and 50 in rostral, mid, and caudal divisions of the PVN in males and females. Vascular changes relative to disruption of the R1 subunit of the GABA(B) receptor were evaluated at P8 and P20. For defined regions of interest within the PVN there were age dependent increases in blood vessel lengths and branching from P8 to 20 to 50 with the most notable increases in the middle region. Loss of GABA(B) receptors did not influence vascular characteristics at P8 in any region, but by P20 there was significantly (20%) less blood vessel length and branching in the mid-PVN region vs. wild type. These findings suggest that the loss of GABA(B) signaling may lead to a late developing defect in angiogenesis. The loss of vascularity with defective GABA(B) signaling suggests that neurovascular relationships in the PVN may be an important locus for understanding disorders of the hypothalamic-pituitary-adrenal axis with potential impact for psychiatric mood disorders along with other comorbid disorders that may be regulated by cells in the PVN.

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress

“…These findings may reflect deficits in cerebral circulation and/or blood-brain barrier permeability in the PVN, effects that would have significant impact on neuroendocrine function (36,37). Furthermore, the PVN is one of the most highly vascularized regions in the brain, suggesting that it may be particularly susceptible to developmental changes in circulation or permeability (38). This heightened plasticity of stress homeostatic mechanisms to transgenerational reprogramming could confer a selective advantage or disadvantage depending on environmental conditions.…”

Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease

“…Given the pivotal role of the PVN in HPA axis outflow, it is perhaps not surprising that GABA may play role(s) in prenatal stress models, not only for PVN neuronal development but also PVN vasculature, suggesting potential links between MDD and CVD risk. As we recently demonstrated, PVN development is regulated by glucocorticoids and GABA, with females being particularly vulnerable to GABA disruption in PVN neuronal (McClellan et al, 2010; Stratton et al, 2011) and vascular development (Frahm et al, 2012). …”

“…Surprisingly, little is known about the development of PVN vascularity (Menendez and Alvarez-Uria, 1987). However, our recent studies on PVN development demonstrate that the remarkable vascularity of the PVN in mice develops over the first three weeks of postnatal life and can be regulated by neurotransmitter signaling (Frahm et al, 2012). The timing occurs after most forebrain vasculature is established, and thereby identifies a secondary angiogenic period as a potential critical feature for PVN development.…”

“…In fact, VEGF is found in high density in PVN (Alonso et al, 2005), one of the most highly vascularized brain regions (Finley, 1937; Menendez and Alvarez-Uria, 1987; Frahm et al, 2012), and in hippocampus (Newton et al, 2003). It has also been found to mediate the effect of BDNF on antidepressant treatment in MDD in the hippocampus (Cao et al, 2004; Warner-Schmidt and Duman, 2007), suggesting a neurogenic role for VEGF in the adult hippocampus in MDD.…”

Hormonal Programming Across the Lifespan

“…While this has been known for over 70 years [50], there are few studies of its development and none on its potential regulation. Using the GABA B receptor subunit knockout mouse noted above, it is clear that GABA signaling can alter PVN vascularization [51] and it is likely that several other factors can as well. In general, the vascular density appears to more often be greater in females, although there is significant variability.…”