William J Pearce

• PhD in Physiology
• Loma Linda University

The rate-limiting enzyme for vascular contraction, Myosin Light Chain Kinase (MLCK), phosphorylates regulatory myosin light chain (MLC 20 ) at rates that appear faster despite lower MLCK abundance in fetal compared to adult arteries. This study explores the hypothesis that greater apparent tissue activity of MLCK in fetal arteries is due to age-dep...

The present study explored the hypothesis that an adverse intrauterine environment caused by maternal undernutrition (MUN) acted through corticosteroid-dependent and -independent mechanisms to program lasting functional changes in the neonatal cerebrovasculature and vulnerability to mild hypoxic-ischemic (HI) injury. From day 10 of gestation until...

Changes in vascular contractility are among the most important physiological effects of acute and chronic fetal hypoxia. Given the essential role of Myosin Light Chain Kinase (MLCK) in smooth muscle contractility, and its heterogeneous distribution, this study explores the hypothesis that subcellular changes in MLCK distribution contribute to hypox...

Intracerebral hemorrhage (ICH) remains one of the most debilitating types of stroke and is characterized by a sudden bleeding from a ruptured blood vessel. ICH often results in high mortality and in survivors, permanent disability. Most studies have focused on neuroprotective strategies designed to minimize secondary consequences and prevent furthe...

Heme oxygenase-1 (HO-1) is an inducible enzyme that catabolizes heme into biliverdin (which is converted to bilirubin), carbon monoxide, and free iron. HO-1 and its downstream molecules have antioxidant and anti-inflammatory functions, making the effects of HO-1 difficult to predict. It is unknown if HO-1 expression has neuroprotective or neurodege...

This study explored the hypothesis that late gestational reduction of corticosteroids transforms the cerebrovasculature, and modulates postnatal vulnerability to mild hypoxic-ischemic (HI) injury. Four groups of Sprague-Dawley neonates were studied: 1) Sham-Control; 2) Sham-MET; 3) HI-Control; 4) HI-MET. Metyrapone (MET), a corticosteroid synthesis...

We introduce a novel protocol to stain, visualize, and analyze blood vessels from the rat and mouse cerebrum. This technique utilizes the fluorescent dye, DiI, to label the lumen of the vasculature followed by perfusion fixation. Following brain extraction, the labeled vasculature is then imaged using wide-field fluorescence microscopy for axial an...

MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs with 21-25 nucleotides in length, and play an important role in regulating gene expression at the post-transcriptional level via base-paring with complementary sequences of the 3' untranslated region of the target gene mRNA, leading to either transcript degradation or translation in...

Intranasal recombinant osteopontin (OPN) has been shown to be neuroprotective in different models of acquired brain injury but has never been tested after traumatic brain injury (TBI). We used a model of moderate‐to‐severe controlled cortical impact in male adult Sprague Dawley rats and tested our hypothesis that OPN treatment would improve neurolo...

Traumatic brain injury (TBI) results in damage to the cerebral vasculature and is often associated with hypoperfusion, edema, hemorrhage, and cell death. While numerous studies have revealed that the cerebral vasculature is injured after TBI, there are scant studies looking at repair of the vessel network following brain injury. At present there ar...

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 con...

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant a...

Aortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffenin...

In this issue of Acta Physiologica, Ansar et al. study the role of MAPK in ischemic stroke1. The mitogen activated protein kinase (MAPK) pathways have long been recognized as major common mediators of stimuli that lead to cell growth and proliferation in numerous cell types. MAPK pathways also influence diverse cell processes such as differentiatio...

We previously reported that traumatic brain injuries (TBI) alter cerebrovasculature near the injury site in rats, followed by revascularization over a 2-week period. Here, we tested our hypothesis that male and female adult mice have differential cerebrovascular responses following a moderate controlled cortical impact (CCI). Using in vivo magnetic...

Platelet-derived growth factor receptor-β (PDGFR-β) has been reported to promote phenotypic transformation of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the role of the PDGFR-β/IRF9/SIRT-1/NF-κB pathway in VSMC phenotypic transformation after subarachnoid hemorrhage (SAH). SAH was induced using the endovascul...

The poster examines how the cerebral vessels respond in the course of 7 days following a moderate TBI and what role the Wnt/β-catenin signaling plays in the vascular repair process.

7 Center for Perinatal Biology, Loma Linda University, Loma Linda, CA 92350 USA Abstract The role of the cerebrovascular network and its acute response to TBI is poorly defined and emerging evidence suggests that cerebrovascular reactivity is altered. We explored how cortical vessels are physically altered following TBI using a newly developed tech...

Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/β-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature re...

Recirculation, from arterial inflow routes through venous outflow pathways, was conceptualized in stroke research 50 years ago. As new technologies were developed, blocked arteries could be reopened, capillaries could be reperfused, and the use of recanalization and reperfusion grew to dominate therapeutic strategies. These approaches overwhelmingl...

Hypoxic environments at high altitude have significant effects on kidney injury. Following injury, renal primary cilia display length alterations. Primary cilia are mechanosensory organelles that regulate tubular architecture. The effect of hypoxia on cilia length is still controversial in cultured cells, and no corresponding in vivo study exists....

In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that...

Long-term hypoxia (LTH) attenuates nitric oxide (NO) induced vasorelaxation in ovine middle cerebral arteries. Because cGMP-dependent protein kinase (PKG) is an important mediator of NO signaling in vascular smooth muscle, we tested the hypothesis that LTH diminishes the ability of PKG to interact with target proteins and cause vasorelaxation. Prom...

*Anatol Manaenko and Peng Yang contributed equally to this work.Intracerebral hemorrhage (ICH) represents the deadliest subtype of all strokes. The development of brain edema, a consequence of blood-brain barrier (BBB) disruption, is the most life-threatening event after ICH. Pathophysiological conditions activate the endothelium, one of the compon...

This study explores the hypothesis that intracerebral hemorrhage (ICH) promotes release of diffusible factors that can significantly influence the structure and function of cerebral arteries remote from the site of injury, through action on platelet-derived growth factor (PDGF) receptors. Four groups of adult male Sprague Dawley rats were studied (...

Objective: Vitamin D status increases during healthy mammalian pregnancy, but the molecular determinants remain uncharacterized. The first objective of this study was to determine the effects of pregnancy and the second objective was to examine the role of chronic hypoxia on vitamin D status and metabolism in an ovine model. Approach and Results:...

Traumatic brain injuries (TBI) often involve vascular dysfunction that leads to long-term alterations in physiological and cognitive functions of the brain. Indeed, all the cells that form blood vessels and that are involved in maintaining their proper function can be altered by TBI. This Review focuses on the different types of cerebrovascular dys...

BACKGROUND Previous studies have shown that chronic hypoxia ablates the endothelium‐dependent NO‐mediated vasorelaxation pathway of which protein kinase G (PKG) is a key effector. Direct activation of PKG likewise demonstrates attenuated PKG influence on 5HT‐induced vascular tone in chronic hypoxic cerebral arteries compared with normoxic arteries....

INTRODUCTION Abundant evidence suggests an important role of glucocorticoids (GC) in cerebral injury produced by ischemia, particularly in neonates. The majority of this evidence is focused on the role of GC in neuronal, glial, and endothelial acute responses to injury. In addition to involvement in acute responses, however, GC also play a critical...

Subarachnoid hemorrhage (SAH) is a common injury involving a complex and incompletely understood etiology. The present study explores the hypothesis that brain injury caused by SAH involves major changes in the structure and function of small cerebral arteries, in addition to its well‐known effects on neurons, glia and capillary endothelium. To eva...

Chronic exposure of in‐utero fetuses to severe hypoxia induces maladaptive changes in vascular structure and function, and elevates postnatal susceptibility to metabolic, endocrine, cardiovascular diseases. Correspondingly, multiple studies have demonstrated that chronic hypoxia depresses vascular contractility through mechanisms that remain to be...

Background and purpose: Recombinant osteopontin (rOPN) has been reported to be neuroprotective in stroke animal models. The purpose of this study is to investigate a potential role and mechanism of nasal administration of rOPN on preserving the vascular smooth muscle phenotype in early brain injury after subarachnoid hemorrhage (SAH). Methods: O...

Objective: Platelet-derived growth factor-BB activates platelet-derived growth factor receptor-β and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1, which can ampl...

Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca2+-activated K+ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca2+. Intrauterine chronic hypoxia (CH) may reduce vasorela...

We previously showed that in vitro sensitivity to dexamethasone stimulation in human endothelial cells is positively regulated by the glucocorticoid receptor (NR3C1, GR). The present study determined the role of differential GR transcriptional regulation in glucocorticoid sensitivity. We studied 25 HUVECs that had been previously characterized as d...

The purpose of this study was to examine the hypothesis that excess maternal glucocorticoids in response to maternal undernutrition programs the expression of extracellular matrix (ECM) components potentially by miR-29c. We measured the expression of mRNA (qRT-PCR) and protein (Western blot) for collagen 3A1, collagen 4A5 and matrix metalloproteina...

Fetal hypoxia triggers compensatory angiogenesis and remodeling through mechanisms not fully elucidated. In response to hypoxia, hypoxia inducible factor drives expression of cytokines that exert multiple effects on cerebral structures. Among these, the artery wall is composed of a heterogeneous cell mix, and exhibits distinct patterns of cellular...

The present study tests the hypothesis that postnatal changes in contractile protein organization drive changes in MLC20 phosphorylation that contribute to age‐related changes in contractility. In homogenates, MLCK exhibited similar enzyme velocities in fetal and adult ovine carotid arteries. To compare MLCK activity in situ, common carotids were p...

This study explores the hypothesis that chronic hypoxia alters the expression and intracellular coupling of endothelin receptors to induce phenotypic transformations of smooth muscle cells within the arteries of fetal cerebrovasculature. Endothelium‐denuded middle cerebral arteries (MCAs) harvested from term fetuses of pregnant adult sheep kept at...

This study explores the hypothesis that chronic hypoxia modulates endothelial regulation of smooth muscle phenotype and function in fetal cerebral arteries. Endothelium denuded and intact middle cerebral arteries harvested from term fetuses from ewes kept at sea level (Normoxic) or 3, 820 m (Hypoxic) altitudes for the last 110 days of gestation wer...

OBJECTIVE Chronic hypoxia attenuates the ability of PKG to induce vasorelaxation in serotonin‐contracted ovine carotids, and more so in fetal than adult arteries. The present investigation examines the hypothesis that alterations in the BK channel and other PKG kinase substrates contribute to hypoxic attenuation of PKG‐dependent vasorelaxation in t...

The sympathetic perivascular innervation has long been suggested to exert trophic influences on cerebral arteries, particularly during hypoxic adaptation. Although most of this effect has been attributed to the actions of norepinephrine, sympathetic nerves also co‐release NPY together with norepinephrine. This study tests the hypothesis that NPY re...

circadian rhythms permeate virtually all life. In mammals, these rhythms are evident in circulating glucose and hormone levels, immune cell abundance and activity, whole body metabolic rate and temperature, and blood pressure. Correspondingly, the function and activity of all major organ systems

Recent studies suggest that VEGF contributes to hypoxic remodeling of arterial smooth muscle, although hypoxia produces only transient increases in VEGF that return to normoxic levels despite sustained changes in arterial structure and function. To explore how VEGF might contribute to long-term hypoxic vascular remodeling, this study explores the h...

For more than three decades, research programs in the Center of Perinatal Biology have focused on the vascular biology of the fetal cerebral circulation. In the 1980s, research in the Center demonstrated that cerebral autoregulation operated over a narrower pressure range, and was more vulnerable to insults, in fetuses than in adults. Other studies...

Prenatal, intra‐partum or post partum exposure of a fetus to hypoxia results in structural and functional changes in cerebral arteries, known as remodeling. Sympathetic nerves have been suggested to contribute to this process. Whereas NE is suggested as the major mediator of adrenergic effects, our preliminary experiments show that there is a guane...

As we have previously shown (PMID: 23325408), chronic hypoxia (CH) dramatically reduces MLCK abundance in fetal common carotid arteries without proportionate loss of contractility. The present study explores the hypothesis that CH preferentially decreases MLCK not associated with MLC and thereby preserves contractility. Common carotid arteries from...

To better understand how hypoxia‐induced vascular remodeling alters intracellular responses to ET‐1, we hypothesized that chronic hypoxia alters ET‐1 induced phenotypic transformation in arterial smooth muscle cells within the fetal cerebrovasculature. Endothelium denuded middle cerebral arteries (MCA) harvested from term fetuses of pregnant adult...

Cerebral arteries adapt to chronic hypoxia by altering the phenotypes of the plastic and heterogeneous population of cells in the artery wall. Perivascular nerves also undergo differentiation during hypoxia and alter vasotrophic effects on arteries. Here we test the hypothesis that nerves from the superior cervical ganglia (SCG) mediate hypoxic rem...

Although the effects of prenatal under-nutrition on adult cardiovascular health have been well studied, its effects on the cerebrovascular structure and function remain unknown. We used a pair-fed rat model of 50% caloric restriction from day 11 of gestation to term, with ad libitum feeding after birth. We validated that maternal food restriction (...

To test the hypothesis that inhibition of offspring angiogenesis by maternal undernutrition (MUN) is mediated by maternal glucocorticoids, 3 groups of dams were studied: controls received ad libitum food; MUN dams were food restricted by 50% from day 10 of gestation; and metyrapone (MET) dams were food restricted and treated with 0.5 mg/mL of MET,...

Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. B...

Rapid postnatal growth and differentiation of fetal arterial smooth muscle is coordinated by a cacophony of growth factors, one of the most important of which is vascular endothelial growth factor (VEGF). In fetal arterial smooth muscle, VEGF influences both the expression and intracellular organization of contractile proteins and helps mediate hyp...

Recent studies suggest that vascular endothelial growth factor (VEGF) can modulate smooth muscle phenotype and consequently the composition and function of arteries upstream from the microcirculation where angiogenesis occurs. Given that hypoxia potently induces VEGF, the present study explores the hypothesis that in fetal arteries VEGF contributes...

In addition to its role in angiogenesis, VEGF may also contribute to arterial remodeling, possibly through activation of VEGF receptors on sympathetic nerves leading to altered trophic input to the arterial wall. To test this hypothesis normoxic and chronically hypoxic fetal sheep (110 days at 3820m) underwent unilateral superior cervical sympathec...

Objective: Chronic therapy with synthetic glucocorticoids has been associated with cardiovascular side effects, although differential interindividual susceptibility to glucocorticoids has been observed. The objective of this study was to identify the molecular mechanisms leading to differential glucocorticoid responses in endothelial cells. Appro...

Chronic hypoxia attenuates soluble guanylate cyclase-induced vasorelaxation in serotonin (5-HT) contracted ovine carotid arteries. Because PKG mediates many effects of soluble guanylate cyclase activation through phosphorylation of multiple kinase targets in vascular smooth muscle we tested the hypothesis that chronic hypoxia reduces the ability of...

The concept of the neurovascular unit as the key brain component affected by stroke is controversial, because current definitions of this entity neglect mechanisms that control perfusion and reperfusion of arteries and arterioles upstream of the cerebral microcirculation. Indeed, although definitions vary, many researchers consider the neurovascula...

Chronic hypoxia increases Vascular Endothelial Growth Factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and non-pregnant ewes were maintained at sea level (normoxia...

Hypoxic increases in VEGF contribute to growth of perivascular nerves, which exert potent trophic effects on cerebral arteries. Here we explore the hypothesis that the perivascular sympathetic innervation (PSI) mediates hypoxic changes in the smooth muscle phenotype, structure and function of fetal lamb middle cerebral arteries (MCA). A right super...

To better understand how chronic hypoxia causes vascular remodeling, we hypothesized that hypoxic increases in VEGF alter cerebrovascular contraction through direct actions on both endothelium and arterial smooth muscle. Endothelium intact (E+) and denuded (E−) middle cerebral arteries (MCA) harvested from term fetuses and non‐pregnant adult sheep...

OBJECTIVE Chronic hypoxia attenuates endothelium‐dependent vasodilatation, more in fetal than adult arteries. Here we examine the hypothesis that these effects involve inhibition of PKG activity and reduced BK channel activity. METHODS Pregnant and Non‐Pregnant ewes were held at sea level (normoxic) or at 3820m (hypoxic) for the final 110 days of...

Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca(2+)) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, th...

Long-term hypoxia (LTH) can increase serotonin (5-HT) signaling as well as extracellular calcium entry in adult rodent pulmonary arteries (PA), and 5-HT is associated with pulmonary hypertension. Because LTH, 5-HT, and calcium entry are related, we tested the hypothesis that LTH increases 5-HT-mediated PA contractility and associated calcium influx...

Genome-wide association studies of stroke have revealed a polygenomic pathology in which contributions from individual genes are highly variable. This variability appears to be due at least in part to contributions from epigenetic mechanisms that fall into three main categories. The first includes mechanisms that mediate DNA methylation and attenua...

The purpose of this chapter is to give an overview of current thinking regarding the mechanisms of hypoxic and hypercapnic cerebral vasodilatation. Given the great breadth of this topic, the chapter will focus primarily on the general hypotheses proposed to explain these effects, which fall into three main groups. The first and oldest of these is t...

The present study explores the hypothesis that arterial smooth muscle cells are organized into layers with similar phenotypic characteristics that vary with the relative position between the lumen and the adventitia due to transmural gradients in vasotrophic factors. A corollary hypothesis is that vascular endothelial growth factor (VEGF) is a fact...

The mammalian fetus is highly adapted for growth in a low-O(2) environment in which arterial O(2) tensions average near 30 mm Hg. Acute decreases in O(2) tension below this value elicit vasodilatation, but the responses are blunted compared to those observed in adults. Chronic hypoxia in the fetus stimulates a pattern of cerebrovascular remodeling...

In light of evidence that immature arteries contain a higher proportion of noncontractile smooth muscle cells than found in fully differentiated mature arteries, the present study explored the hypothesis that age-related differences in the smooth muscle phenotype contribute to age-related differences in contractility. Because Ca(2+) handling differ...

To test the hypothesis that relations between myogenic tone and cytosolic Ca++ are enhanced by myofilament Ca++ sensitization but attenuated by high proportions of non‐contractile smooth muscle cells, in immature compared to mature rat cerebral arteries, three protocols were performed in middle cerebral arteries (MCA) from P14 and adult rats. Myofi...

NO‐dependent relaxation of ovine cerebral arteries is enhanced during postnatal maturation but is attenuated by acclimatization to high altitude. Because NO‐mediated vasorelaxation is mediated by activation of PKG, which in turn activates large conductance BK channels, we hypothesized that the effects of both maturation and chronic hypoxia on NO‐de...

Double label confocal studies of smooth muscle α‐actin and SM2 myosin indicate significantly greater colocalization between these markers in adult than neonatal arteries revealing that the fraction of non‐contractile smooth muscle cells is greater in immature than mature arteries. To explore the hypothesis that age‐related differences in phenotype...

The aim of this study was to test the hypothesis that maternal undernutrition (MUN) alters offspring vascular expression of micro-RNAs (miRNAs), which, in turn, could regulate the expression of a host of genes involved with angiogenesis and extracellular matrix remodeling. The expression of miRNA and mRNA in the same aortic specimens in 1-day-old (...

The contribution of sympathetic nerves arising from the superior cervical ganglia (SCG) toward the growth and function of cerebral blood vessels is pertinent throughout maturation as well as in response to cardiovascular stress imposed by high-altitude long-term hypoxia (LTH). The function of SCG sympathetic neurons is dependent on intracellular Ca...

Not Applicable Key words: GnRH, Placentation, CXC Chemokines, Trophoblasts, Implantation.

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the prim...

There is a recent focus on embolization of the portal vein by transplanted islets as a major cause of early graft loss. The resultant ischemia causes necrosis or apoptosis of cells within the liver. Thus, noninvasive assessment of the liver receiving the islet transplant is important to evaluate the status islet grafts. This study used noninvasive...

Chronic hypoxia (CH) can cause structural changes in the lung where the smooth muscle layer thickens due to myocyte hypertrophy and hyperplasia. CH compromises pulmonary arterial (PA) contractility and Ca ²⁺ ‐signaling in the sheep fetus as well as the non‐pregnant ewe. Yet, the influence of CH on sheep PA and myocyte structure is unresolved, which...

The pulmonary vasculature regulates lung blood flow in order to maintain blood oxygenation. However, chronic hypoxia (CH) such as that induced by high‐altitude exposure leads to changes and dysfunctions in the pulmonary vasculature. Serotonin (5‐HT) is an inflammatory mediator that triggers cytosolic Ca ²⁺ increases and pulmonary arterial smooth mu...

Chronic hypoxia (CH) influences Ca ²⁺ ‐dependent pulmonary arterial (PA) reactivity, and enhanced vasoreactivity is a risk factor in pulmonary disease. Using wire‐myography, Western immunoblot, and Ca ²⁺ imaging approaches of PA isolated from adult sheep housed under normoxic conditions or at 12,470 feet for ~ 110 days (CH), the hypothesis that CH...

Agonists can induce pulmonary arterial contractility through membrane depolarization and resultant cytosolic Ca ²⁺ increases. The specific mechanism(s) involved in the depolarization process remain controversial, but evidence indicates calcium‐activated chloride channels (ClCa) are pivotal. Our previous investigations show the role of L‐type Ca ²⁺...