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Vasculature and innervation of skin

PRESENTER : DR ANSHUL AGRAWAL

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VASCULATURE OF SKIN• Blood vessels of the skin are formed embyrologically by an intricate

network of mesenchymal cells that come to surround arbonizing spaces.

BLOOD VESSELS

superficial deep plexus venules

plexus

ALL OF WHICH ARE CONNECTED BY

COMMUNICATED BLOOD VESSELS

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• Communicating vessels arise from and lead back to arteries and veins that lie within the septa of the subcutaneous fat.

• Deep plexus: lower part of reticular dermis

• Superficial plexus: upper part of reticular dermis , just beneath the papillary dermis (sub papillary plexus)

• Superficial and deep plexus lie parallel to the skin surface

• Communicating vessels lie perpendicular to it

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• Superficial plexus: arcade of capillary loop upward into each dermal papillae.

• Endothelium of those capillary stain well for alkaline phosphatase.

• Capillary loop consists of ascending arterial component ----hairpin turn----descending venous limb.

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VENOUS PORTION EMPTIES INTO

Postcapillary venules of superficial plexus

Dermal communicating venules

Large venules of deep plexus

Small veins of subcutaneous fat.

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• Superficial and deep plexus anastomose richly thoughout the dermis

• Anastomoses is developed most highly at upper part of dermis and around folliculo-sebaceous-apocrine units and eccrine glands.

• This arrangement permits development of alternative channels for preferential blood flow if other routes become blocked.

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Vascular development• During embryogenesis, the first blood vessels are formed through

Vasculogenesis.

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EXTRAEMBRYONIC MESODERM OF YOLK SAC

BLOOD ISLANDS OF HEMANGIOBLASTS (CLUSTERS OF EPITHELIOID CELLS)

OUTER CELLS INNER CELLS

ANGIOBLASTPRIMITIVE

HEMATOPOETIC CELLS

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ANGIOGENESIS• Sprouting of the new blood vessels from existing primordial vessels,

represents a major mechanism of new blood vessel formation.

• The Tie- 2 receptor tyrosine kinase , expressed on vascular endothelial cells ,plays a crucial role in sprouting and remodeling during early embryonic angiogenesis.

• Pericyte derived angiopoieten 1 (Ang-1) activates the Tie-2 receptor , whereas Angiopoietin 2 acts as inhibitor of Ang-1

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• Angiogenesis occurs as :

1. The sprouting outgrowth of new capillaries from pre-existing post capillary venules

2. Non-sprouting remodling of pre-existing vessels either through circumferential growth/vascular enlargement or through the formation of intravascular endothelail cell pillars

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• Stepwise induction of angiogenesis:

1. Induction of microvascular hyperpermeability

2. Enzymatic degradation of vascular basement membrane and interstitial matrix

3. Endothelial cell migration via integrin receptors on activated endothelial cells interacting with native or degraded matrix molecules.

4. Endothelial cells proliferation

5. Formation of mature blood vessels

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Histology of blood vessels

Arteries in the subcutaneous fat and larger arterioles in the deep part of the dermis consist of:

1. INITIMA: composed of endothelial cells

and internal elastic membrane.

2. MEDIA: contains collagen , non layered

elastic fibers, and several concentric layers

of smooth muscles which in arteries

are bound by external elastic membrane .

3. ADVENTITIA: constitutes fibrocytes,

type III collagen and elastic fibers.

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• Arterioles in the superficial dermis do not posses an internal or external elastic membrane and their wall contains discontinuos layers of elastic fibers and smooth muscle cells.

• Ascending segment of capillary loop consist of single layer of endothelial cells that line a narrow lumen and in turn is surrounded by discontinuous layer of pericytes.

• Endothelial cells and pericytes are enveloped by continuous homogeneous appearing basal lamina.

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• Descending venous loop is wider, pericytes are more numerous and basal lamina becomes multilayered.

• Post capillary venules resemble capillaries, their walls consisting only of endothelial cells ,pericyte and basal lamina surrounded by thin zones of type III collagen fibers. Walls of larger venules posses variable amount of smooth muscle and elastic fibers , but no elastic membrane .

• All arterioles , capillaries and venules in dermis are encircled by flat adventitial cells: Veil cells whose exact nature is unclear and is situated entirely outside the wall of a vessel, demarcating it from surrounding dermis. They are seen infrequently around vessels of subcutaneous fat.

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Capillaries of the skin are continuous type and when viewed through electron microscope , adjacent endothelial cells that constitute them appear to be connected to one another by specialized intercellular junctions

Endothelial cells contain mostly of• cytoplasmic filaments: diameter 7.5 and 10 nm • Pinocytotic vesicles that measure 50 – 70 nm in diameter

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Exchange of fluid and small water soluble molecules from lumina of continuous capillaries to pericapillary tissue occurs mainly through pinocytotic vesicles .

These vesicles form at the luminal membrane of an endothelial cell, pass through the cytoplasm ,and discharge their contents in contraluminal membrane .

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In contrast, fenestrated venous capillaries situated within the adventitial dermis adjacent to eccrine glands and follicular bulbs, allow passage of larger molecules through gaps between adjacent endothelial cells.Intercellular gaps may be widened by contraction of actin filaments 7.5nm in diameter , within cytoplasm of endothelial cells

Hence, continuous capillaries are permeable to small, water soluble molecules mainly by way of micropinocytic route, whereas fenestrated capillaries also allow interendothelial transport of larger molecules such as plasma proteins.

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• Postcapillary venules, the predominant type of vessel within the upper part of dermis, are most permeable of the cutaneous blood vessels and frequently are sites of pathologic changes of inflammatory skin diseases.

• In post capillary venule, pericytes and endothelial cells make contact with one another at many points over their entire surfaces.

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• Single pericyte forms tight junction with 2-4 subadjacent endothelial cells through breaks in multilaminated basement membrane.This contact is rich in fibronectin .

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• The presence in pericyte of contractile protein isomyosins, coupled with complex cytoplasmic interdigitations , supports the concept that pericytes are major contractile cells for effecting interendothelial cell gaps in post capillary venular segments where the inflammatory events take place

• In addition vaso active substance such as prostaglandins and histamine released by leucocytes , mast cells or platelets increase venullar permeability by inducing contraction of endothelial cells and pericytes with resultant widening of intercellular spaces .

• This process favors deposition of immune comlpexes within the walls of post capillary venules in conditions such as leuckocytoclastic vasculitis and allows extravasation of fluids and inflammatory cells in the surrounding connective tissue

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Glomus bodies• Specialized arteriovenous shunts

• Allow blood to be shunted from arteriole to venule , thereby bypassing the capillary bed and increasing the rate and volume of regional blood flow

• They are most abundant in the dermis of acral skin i.e nail beds, finger toes,ears and nose

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• Arterial segment of glomus body termed as Sucquet-Hoyer canal,has narrow lumen and thick wall that consists of endothelium surrounded by 3-6 contractile glomus cells

• Venous segment is thin walled and has wide lumen that drains into subpapillary venule

• These are modified smooth muscle cells that possess uniform ovoid nuclie and pale staining cytoplasm with rindistinct cell margins

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• The total volume of the blood that flows through the skin exceeds by far the metabolic requirement

• Primary functions of cutaneous vessel is related to control of temperature and to regulation of blood pressure.

• In an thermally neural environment, the skin receives 5-10% of cardiac output and this may increase to upto sevenfold under conditions of severe heat stress or decrease to zero in extremely cold environments

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• In acral regions vessels are controlled predominantly by unmyeilinated adrenergic sympatatic nerves.

• These tonically active vasoconstrictor nerve fibers are the efferent arm of

1 . Baroreflexes that originate in both arterial and cardiopulmonary baroreceptors

2. Reflex baro responses to operate posture and exercise

3. Chemoreceptor reflexes

4. Thermo regualtory reflexes

• Non acral skin: also possess a neurogenic vasodilator system that is an a efferent arm of reflexes originating in hypothalamic thermo receptors

Vascular tone and its regulation

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FACTORS AFFECTING THE CALIBER OF ARTERIOLESVasoconstrictors: Vasodilators:

Increased adrenergic dischargeCirculating catecholamines (expect epinephrine in skeletal muscles)Circulating Angiotgensin II, Locally released Serotonin Decreased local temperatureIncreased carbon dioxidetension

Decreased adrenergic dischargeActivation of cholenergic dilatorsEthanolHistaminesKininsDecreased oxygenProstaglandins of E- series Local heating of the skin.

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Lymphatics• Lymphatic vessels were first described in the seventeenth century by gasparo aselli

as ‘’lacteae venae ‘’i.e milky veins• The cutaneous lymphatic system develops in parallel with blood vascular system

through a process termed lymphangiogenesis.• The lymphatic system is composed of vascular network of thin walled capillaries

that drain protein rich lymph from extra- cellular space and maintain a crucial role in maintenance of normal tissue pressure

• lymphatic vessels also play a vital role in mediating the trafficking of immune cells from the skin to regional lymph nodes , and in metastatic spread of cutaneous malignancies

• Histopathology: lympahtic capillaries are lined by continuous single layer of overlapping endothelial cells and lack continuous basement membrane

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• The lymphatic vessels of skin form two horizontal plexuses.• Superficial collects lymph from lymphatic capillaries that can extend into the

dermal papilaae and is located in close vicinity to superficial cutaneous arterial plexus

• Vertical lymphatic vessels connect superficial vessels with larger collecting vessels in lower dermis and upper sub cutis

• the deep lymphatic vessels are located below the deep arterial system and contain valves to ensure unidirectional fluid transport

• Finger tips, palms and soles,the scrotum and foreskin appear to have more abundant lymphatic network.

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Clinical aspect

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Cutaneous vascular responses

• Erythema• Flushing• Blushing

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Erythema anuulare centrifugum• Erythema chronicum migrans• Erythema marginatum rheumaticum

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Telangiectases

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Erythema multiforme

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Urticaria

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Angioedema

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Idiopathic thrombocytopenic purpura

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Disseminated intravascular coagulation (DIC)

42Acroangiodermatitis

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• Purpura’s:• Pigmented purpura dermatoses• Painful bruising syndrome• Contact pupura

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Vasculitis1. Large vessel vascultis

2. Medium vesssel vascultis3. Small vessel vasculitis

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• Thromboangitis obliterans• Erythromelalgia• Venous ulcers• Deep vein thrombosis

• Disorders of lymphatics:1. Lymphedema2. Lymphangioma circumscriptum3. Cavernous lymphangioma4. Lymphangiectases

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NERVESSkin is innervated by a dense, three dimentional network of highly specialized

afferent sensory and efferent autonomic nerve branches.

Part of 2 major systems: • somatic sensory • Autonomic motor

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Somatic sensory

• Sensory innervation follows well-defined dermatomes with some overlap between adjacent dermatomes

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Somatic sensory• The afferent sensory neurons are unipolar and branch off with a single axon

travelling towards the skin.

• Sensory nerves not only function as an afferent system to conduct stimuli back from the skin to the CNS, but also act in an efferent neurosecretory fashion, releasing neuropeptides with important visceromotor, infl ammatory and trophic effects on skin

• Somatic sensory system mediates the sensations of pain ,itch, temperature, light touch, pressure, and vibration, proprioception and epicritical or discriminative sensations of touch

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• Cutaneous sensory receptors are classified into 2 groups :

1. Specialized receptors :possess terminal nerve endings that are surrounded by distinct lamellar condensations of connective tissue and shwann cells ( e.g pacini corpuscles , meissners corpuscles and mucocutaneous end organs )

2. Unspecialised receptors: do not possess distinct structural features.

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Pacini corpuscles • Situated chiefly on weight bearing surfaces in the deep portion of the

dermis and the subcutaneous fat

• Numerous in the oral lips, penis,clitoris,nipples

• Each corpuscle measures about 0.8 x 1.5 mm and is supplied by myelinated axon that makes several turns before it enters the concentrically layers connective tissue capsule that envelops the sensory terminal.

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• The concentric lamellae consist of flattened cells( laminar cells) that probably are modified shwann cells

• Spaces filled with fluid separate thin layers of adjacent laminar cells with their associated connective tissue, in the outer portion of pacini corpuscle

• In central core bulbous terminal nerve ending, now devoid of its mylein sheath is in direct contact with the innermost laminar cells

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• The lamillar organization of corpuscle may enable it to act as a primary receptor that gives rise to action potentials when its architecture is destorted

• Pacini corpuscle are mechano receptors that primarily detect the sensation of pressure

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Meissner’s corpuscle• Present at tips of dermal papillae on volar skin and are most plentlyful over

fingertips

• Each corpuscle measures about 50 x 150 microns and consists of layers of flattened laminar cells among which some ramify axon terminals derived from myelinated nerves

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• Typically the axons weave back and forth between stacks of lamillae • Under elecron microscope, laminar cells posses basal lamina and at the periphery

of the corpuscle are separated by collgen fibers, elastic fibers and fibrillary intercellular material

• Function: rapidly adapting mechanoreceptors that detect the senstaion of light touch

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Mucocutaneous end organs• Located in subpapillary connective tissue of the glans

penis,prepuce ,clitoris ,labia minora , perianal area ,eyelids and oral lips • In contrast to pacini and meissner corpuscle these cannot be visualized in

sections stained by hematoxylin and eosin .• Measure about 50 microns in diameter and contain loops of loosely wound,

branching axons that form irregular oval masses .

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• There is no ture capsule around a mucocutaneous end organ.

• By ultrastructural examination, seen to be divided into lobullar units that contain axon terminals surrounded by concentric lamellar processess originating from lamellar cells.

• Interlamellar substance at the periphery of a mucocutaneous end organ contains collagen fibers, elastic fibers and other cross banded structures.

• Act as touch receptors

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Unspecialized receptors

• The millions of unspecialzed sensory receptors that supply the skin maybe categorised as follows:

1. Associated with hair follicles

2. Unassociated with hair follicles

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• These fine nerve endings are visualized by light microscope with specialized stains of silver salts, methylene blue or cholinesterase

• Hair follicles are supplied by myelinated sensory nerves that branch extensively

• One ,myelinated axon may supply many hair follicles and each follicle may in turn be supplied by several different axons

• These sensory endings are most numerous just below the level of a sebaceous duct.• Free nerve endings are particularly abundant in the glans penis where they are

found in almost every dermal papillae as well as scattered throughout the deeper dermis .

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• Apocrine and eccrine glands are supplied by unmyelinated adrenergic and cholenergic nerves

• Apocrine secretion is mainly due to adrenergic activity .

• Cholinergic stimulation is responsible for widespread eccrine sweating that occurs as a consequence of attempts to regulate high temperature , whereas adrenergic stimulation eccrine secretion causes perspiration localized to palms and soles , axillae and forehead during emotional stress

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• Three principal fiber groups are recognized in cutaneous nerves and are designated A,B and C. this sequence represents the order of increasing threshold of sensation and decreasing conduction velocity

• Type A fibers are myeilinated and C are unmyeilinated

Fiber type function

A - α Proprioception

A-β(10 an 14 microns) sensations of touch vibration and proprioception

A- γ sensations of light touch and pressure

A- δ sensations of pain, temprature and physiologic itching

B Preganglianic

C(less than 5 microns ) sensations of pain , temprature and pathologic itching

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Autonomic nervous system

• The autonomic nervous system innervates the skin through postganglionic fibres originating in sympathetic ganglia, and terminating in autonomic plexuses that supply sweat glands, blood vessels and arrector pili muscles.

• Histochemically there are two main groups of post-ganglionic nerve fibre in the skin.

1. Firstly, adrenergic fibres synthesize and store catecholamines and norepinephrine (noradrenaline).

2. The second major group consists of the cholinergic Fibres containing acetylcholine. Co-localizing with acetylcholine are ‘secretory’ neuropeptides such as vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM).

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• Autonomic motor nerves control cutaneous vascular tone , pilomotor responses and pseudomtor activity.

• The secretory portion of the eccrine sweat glands, myoepithelial cells and nearby blood vessels are innervated by a basket-weave pattern of nerves, containing predominantly acetylcholine but also significant numbers of fibres containing ‘secretory neuropeptides’ including VIP ,PHM, neuropeptide Y (NPY), calcitonin gene related peptide (CGRP), galanin, atrial natriuretic peptide (ANP) and norepinephrine.

• Adrenergic fibres mediate strong vasoconstriction and arrector pili muscle activity, thus diverting blood from the skin, and pulling hairs into the upright position, in the classical ‘fight or flight’ reaction.

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Merkel cells• Dicovered by friedrich merkel in 1875

• Also called as tastzellen or touch cells

• Appear in fetal skin by 16th week of gestation • Cannot be differentiated by melanocyte or langerhan cells by conventional

microscope

• According to histochemical techniques Similar to other end organs of nerves due to presence of esterases, peptidases, phosphidases and cholinestrases

• With immuno flouroscence stain merkel cells do not react with anti sera 2 neurofilaments or glial acidic fibrillary protein but react with monoclonal antibodies to keratin, neural specific enolase

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• Distinctive features under electron microscope :

elecron lucent cytoplasm rich in organelles,

peripheral cytoplasmic processes that interdigitate

with surrounding keratinocytes,

poorly developed desmosomes ,

delicate cytoplasmic microfilaments ,

many membrane bound granules,with dense core,

lobulated nuclei and intra nuclear rodlets

composed of parallel filaments

surrounded by chromatin free zone

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• Supplied by myelinated nerves that , as they near the epidermis loose their myelin sheaths and continue as unmyelinated axons

• Nerve fibers terminate in flat, miniscus like contacts that are studded along the base of merkel cells

• The basement membrane of axons fused with basal lamina of epidermis• Apposition between merkel cells and axon terminals of specialized

membranes creates a zone that exhibits the typical components of chemical synapse

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• Functions as slow adapting, low threashold touch receptor,

• Detects mechanical deformities of epidermis via cytoplasmic processes and desmosomal attachments to neighboring keratinocytes

• May act to regulate epithelial prolifertaion throught their cytoplasmic contacts with keratinocytes

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• Post- herpetic neuralgia• Neruopathic ulcers• Peripheral neuropathy• Trigeminal trophic syndrome• Heriditary sensory and autonomic neuropathies (type I-V)• Complex regional pain syndrome• Honer’s syndrome• Gustatory hyperhidrosis• Scalp dysaesthesia• Notalgia paraesthetica• Brachioradial pruritis

Clinical aspect

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