Fetal Cerebrovascular Maturation: Effects of Hypoxia

Abstract

The human cerebral vasculature originates in the fourth week of gestation and continues to expand and diversify well into the first few years of postnatal life. A key feature of this growth is smooth muscle differentiation, whereby smooth muscle cells within cerebral arteries transform from migratory to proliferative to synthetic and finally to contractile phenotypes. These phenotypic transformations can be reversed by pathophysiological perturbations such as hypoxia, which causes loss of contractile capacity in immature cerebral arteries. In turn, loss of contractility affects all whole-brain cerebrovascular responses, including those involved in flow-metabolism coupling, vasodilatory responses to acute hypoxia and hypercapnia, cerebral autoregulation, and reactivity to activation of perivascular nerves. Future strategies to minimize cerebral injury following hypoxia-ischemic insults in the immature brain might benefit by targeting treatments to preserve and promote contractile differentiation in the fetal cerebrovasculature. This could potentially be achieved through inhibition of RTK mediated growth factors, such as VEGF and PDGR, which are mobilized by hypoxic and ischemic injury and which facilitate contractile dedifferentiation. Interruption of the effects of other vascular mitogens, such as endothelin and angiotensin-II, and even some miRNA species, also could be beneficial. Future experimental work that addresses these possibilities offers promise to improve current clinical management of neonates who have suffered and survived hypoxic, ischemic, asphyxic, or inflammatory cerebrovascular insults.

Maternal Undernutrition Modulates Neonatal Rat Cerebrovascular Structure, Function, and Vulnerability to Mild Hypoxic-Ischemic Injury via Corticosteroid-Dependent and -Independent Mechanisms

“…Consistent with previous studies [ 35 , 37 ], neonatal hypoxic ischemia significantly shifted the phenotype of cerebrovascular smooth muscle ( Figure 4 B,D). In pups programmed by MUN, mild HI insult promoted contractile differentiation, as indicated by a rightward shift in pixel distributions for αActin colocalization that was most prominent with NM-MHC, but was also significant with SM-MHC ( Figure 4 B,D).…”

“…Specifically, these studies have demonstrated that the phenotype of vascular smooth muscle, as indicated by differential expression of contractile proteins such as smooth muscle αactin and myosin heavy chain isoforms [ 33 , 34 ], can be potently modulated by fetal stress [ 35 , 36 ]. Correspondingly, changes in smooth muscle phenotype in response to the cardiovascular stresses imposed by hypoxia and ischemia, can alter both resting myogenic vascular tone and contractile responses induced by depolarizing stimuli, contractile agonists, and vasodilators [ 37 , 38 ]. A majority of studies of how fetal programming influences postnatal vascular structure and function have focused on mesenteric, renal and femoral arteries and have revealed attenuation of angiogenesis [ 27 ], reduced contractile responses to phenylephrine and norepinephrine [ 39 ], and reduced vasodilatory responses to acetylcholine, bradykinin, sodium nitroprusside, and presumably nitric oxide [ 40 ].…”

Persistent reversed end‐diastolic flow of the middle cerebral artery: A rare and concerning finding

“…If the cerebral resistance continuously rises, a loss of autoregulation of the cerebral blood flow occurs and reverse flow begins. 16,18 The bleeding volume from intracranial hemorrhage causes increased intracranial pressure which interferes with the normal cerebral blood flow and the resistance in turn leads to reversed end-diastolic flow of the MCA. 15 In congenital hydrocephalus, excessive accumulation of cerebrospinal fluid also causes increased intracranial pressure that leads to reversed flow of the MCA.…”

The Neurovascular Unit: Effects of Brain Insults During the Perinatal Period

“…Although not based specifically on the intracerebral capillaries associated with the NVU, these results nonetheless reinforce the notion that vascular responses to chronic hypoxia differ between the perinatal and adult brain. Via effects on contractile mechanisms and receptor affinities, chronic hypoxia attenuates cerebral arterial responses to vasoactive stimuli, impeding cerebrovascular homeostatic maintenance (Pearce, 2018). Chronic hypoxia has also been linked to alterations in sympathetic perivascular innervation, causing changes in cerebrovascular smooth muscle cell differentiation, and subsequently in vascular contractility and functioning (Adeoye et al, 2015;Pearce, 2018).…”

“…Via effects on contractile mechanisms and receptor affinities, chronic hypoxia attenuates cerebral arterial responses to vasoactive stimuli, impeding cerebrovascular homeostatic maintenance (Pearce, 2018). Chronic hypoxia has also been linked to alterations in sympathetic perivascular innervation, causing changes in cerebrovascular smooth muscle cell differentiation, and subsequently in vascular contractility and functioning (Adeoye et al, 2015;Pearce, 2018). Fetal cerebral vasculature also undergoes remodeling in response to in utero chronic hypoxia.…”