Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype

Abstract

Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wild-type mice and in two AD models, the Dutch/Iowa/Swedish triple mutant human amyloid beta-peptide (Abeta)-precursor protein (APP)- expressing mice and APPsw(+/-) mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, Abeta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

“…Hypercontractility in cerebral resistance arterioles was reported in the postmortem brains from Alzheimer's-type dementia patients [30]. The RhoA/Rho kinase signaling pathway in N2A cells activated by 5-HT2A agonist autoantibodies [4] causes Ca2+ sensitization of contraction in vascular smooth muscle cells [31].…”

Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein

“…The observation that vascular responses are normalized in Tg2576 mice lacking Nox2 suggests that Nox2-dependent ROS production is the final common pathway for the vascular alterations induced both by aging and A␤. However, a contribution from the alterations in smooth muscle contractility induced by myocardin in Tg2576 mice cannot be ruled out (37).…”

Role of serum response factor in the pathogenesis of disease

“…83,84 Interestingly, SRF is increased in SMCs of cerebral blood vessels taken from human AD patients, and the elevation in SRF appears to mediate, in part, cerebral hypo-perfusion as reducing SRF with a short-hairpin RNA normalized contractile activity and cerebral blood flow in experimental animals. 85 Furthermore, increases in SRF were recently shown to impede the normal clearance of amyloid b-peptides through direct activation of SREBP2, a known repressor of the major amyloid b clearance receptor, LRP1. 86 Thus, SRF has emerged as a putative target for therapeutic intervention of this devastating disease that is estimated to afflict some 30 million people worldwide.…”