Table 2.

A select list of outstanding research questions remaining in the field of vascular aging for individual major organ systems and the body as a whole

Remaining Questions/Knowledge Gaps for Vascular Aging
Brain
What combination of interventions for lipid species, oxidative stress, and/or inflammation will be most advantageous for restoring cerebrovascular KIR2 function during aging and/or during development of dementia?
What age-related alterations occur for function of TRP channels heterogeneously containing various TRP isoforms (e.g., TRPV4, TRPM3/4/8, TRPA1, TRPC1/3/4/5/6/7) across cerebrovascular smooth muscle and endothelial cells?
How does redox signaling of receptor and ion channel activities governed by ROS (O2•−/H2O2/ HO•) and antioxidant enzymes (glutathione peroxidases, catalase) influence blood flow throughout the brain with aging?
How do gasotransmitters (H2S and CO) influence vascular receptor and ion channel activities in the brain with aging and development of dementia?
In cerebrovascular endothelial cells, why is general TRP-channel mediated Ca2+ entry in response to membrane hyperpolarization robust in males but not in females during old age and advanced conditions of dementia?
How does cerebrovascular aging and the development of dementia influence function of K+ channels on smooth muscle of arteries/arterioles (e.g., BKCa channels) and capillary pericytes (e.g., KATP) across males and females?
Depending on stage of pathology, is Alzheimer’s disease really a problem concerning pre-capillary/capillary blood flow regulation and nutrient delivery to the brain or post-capillary/glymphatic clearance of amyloid, metabolites, and other toxins?
Eye
How does aging and associated diseases (retinopathy, macular degeneration, glaucoma) impact the participation of voltage-gated and nonvoltage-gated Ca2+-permeant channels and K+ channels along retinal arterioles and capillaries?
Is enhanced decay in spreading depolarization (vasoconstriction) or hyperpolarization (vasodilation) along capillaries and arterioles of the eye during disease conditions (e.g., elevated angiotensin II) more attributable to leaky ion channel (e.g., SKCa channel) currents across the membrane or an impairment in overall gap junction expression/function?
As an extension of the brain and central nervous system, can the vasculature of the eye be used for the diagnosis and treatment of cognitive impairment and Alzheimer’s disease?
Skeletal muscle
What are the molecular and cellular mechanisms underlying different ion channel contributions in blood vessels of oxidative (slow twitch) versus glycolytic (fast twitch) muscle fibers and how does that change with aging and disease (e.g., sarcopenia)?
Heart
How does aging and events leading up to cardiac failure influence the metabolic-to-electrical signaling in the microcirculation of the heart among males and females?
Lung
How does aging and development of pulmonary hypertension comprehensively influence the expression and function of receptors and ion channels across smooth muscle and endothelial cells in males and females?
Mesentery
How does the interaction of sensory and sympathetic nerves comprehensively influence activity of vascular receptors and ion channels in the gut during aging and conditions of gastrointestinal inflammation across males and females?
How do various components of the microbiome of the gut influence local vascular signaling in the mesentery and the rest of the body?
How does aging influence vascular receptor and ion channel function of other organ components of the splanchnic circulation such as the liver, pancreas, and spleen across males and females?
Kidney
How does aging influence vascular receptor and ion channel function of the kidney among males and females?
How do systemic and intrarenal renin-angiotensin-aldosterone signaling, perivascular sympathetic and sensory nerves, and intravascular fluid-shear forces shape vascular tone among afferent and efferent arterioles of the pre- and postglomerular apparatus, respectively?
What are all of the molecular and cellular mechanisms involved to explain why the vasoreactivity of afferent arterioles is dependent on membrane potential and the efferent arterioles are not?
Skin
As a valuable non-invasive study model for human subjects, can the skin microcirculation be used as an effective surrogate/index for diagnosis and treatment of vascular health and disease with aging throughout the body as a whole?
Can cutaneous blood flow be modulated using novel TRP and K+ channel agents in aged and/or hypertensive human subjects?
Whole body
How should we distribute our efforts for mechanistic and therapeutic investigation among cardiopulmonary impairment, large artery stiffening, microcirculatory dysfunction, and overall end-organ damage that occur with aging?
Provided similarities for changes in ion channel function (e.g., TRP and K+ channels), are there unifying therapeutic strategies that we can harness for simultaneously treating vascular aging, hypertension, diabetes, obesity, and dementia?
Can novel therapeutic applications such as novel histone deacetylase inhibitors, pharmacological ion channel openers, novel vasoactive gases, mitochondria-targeted antioxidants, or BH4 and vitamin C supplements be used to restore NO bioavailability and/or activate endothelial SKCa and IKCa channels without impacting cell-to-cell coordination of blood flow along vascular resistance networks?
What is the general role of biological sex in receptor/ion channel function of smooth muscle/pericytes versus endothelial cells across organs?
What direct (receptor/ion channel expression) and indirect (e.g., posttranslational modifications) roles do vascular miRNAs play for vascular health during aging?
How is vascular aging manifested for biophysical control of blood flow, nutrient delivery, and metabolite clearance across continuous (brain, skeletal muscle, heart, lungs, skin), fenestrated (mesentery, kidney, pancreas), and sinusoidal (liver, spleen) capillary arrangements?
What direct (receptor/ion channel expression) and indirect (e.g., posttranslational modifications) roles do vascular miRNAs play for vascular health during aging?
What functional changes can be attributed to pre- and posttranslational modifications of the receptor/ion channels themselves versus physical separation from their organellar/molecular modulators?
How does the function of myoendothelial gap junctions alter across individual organs for aging and various chronic diseases?
Relative to other ion channels (e.g., KCa), how do endothelial KIR2 and KATP channels shape electrical conduction of hyperpolarization (vasodilation) and depolarization (vasoconstriction) through gap junctions?
What relative contributions to energy production are made via glycolysis vs. oxidative phosphorylation in endothelial cells and smooth muscle cells across organs during aging?
Outside of the blood circulation, how do the cellular functions of lymphatic vessels change with the aging process while equipped with a fundamentally different structure and signaling arrangement relative to blood vessels?

BK_Ca, high-conductance Ca²⁺-activated K⁺ channels; CO, carbon monoxide; H₂S, hydrogen sulfide; IK_Ca channels, intermediate-conductance Ca²⁺-activated K⁺ channels; K_ATP channels, ATP-sensitive K⁺ channels; K_IR2 channels, inward-rectifying K⁺ channel; ROS, reactive oxygen species; SK_Ca channels, small-conductance Ca²⁺-activated K⁺ channels; TRP channels, transient receptor potential channels; TRPA, TRP ankyrin class TRPC, TRP canonical class; TRPM, TRP melastatin class; TRPV, TRP vanilloid class.