Download Vascular Disorders

In The Name Of
GOD
Vascular Disorders
Fatemeh Mokhtari
Assistant Professor of Dermatology
Vascular Biology
Introduction
• The blood vessels of the skin:
control of body temperature
a conduit for the supply of nutrients and oxygen to the skin
a conduit for the rapid disposal of metabolic waste products
• Blood and lymphatic vessels play essential roles in the development and
progression of:
 skin tumors
in physiologic processes:
 tissue repair
 hair follicle growth
Markers for Blood Vessels
• In normal skin, the most specific markers for cutaneous blood vessels:
CD34
PAL-E
• In normal adult skin, a receptor exclusively expressed on vascular
endothelial cells and maintenance of the mature vascular architecture
Tie-2 receptor
Related Diseases
• Angiogenesis is a characteristic feature of:
 tissue repair
numerous diseases
 inflammatory skin disorders: psoriasis and contact dermatitis
 cutaneous neoplasias: SCC, melanoma and Kaposi sarcoma
 infantile hemangiomas
Related Diseases
• Several other diseases are characterized by prominent visible blood
vessels:
rosacea
BCC
• Genetic mutations that lead to dysfunction of the vascular Tie-2
receptor:
vascular malformations
Vascular Anomalies
• According to the classification system adopted by the
International Society for the Study of Vascular Anomalies
(ISSVA), there are two types of vascular anomalies:
 vascular tumors
 vascular malformations
Vascular Anomalies
• Vascular tumors
cellular proliferation
• Vascular malformations
errors in vascular morphogenesis
 characterized by the type of dysplastic vessels they contain and their
flow properties
Biologic Classification of Vascular Birthmarks
• Vascular Tumors
Infantile hemangioma
Congenital hemangioma (rapidly involuting or non-involuting variants)
Kaposiform hemangioendothelioma
Tufted angioma
 Pyogenic granuloma
Congenital hemangiopericytoma
Spindle cell hemangioma
Biologic Classification of Vascular Birthmarks
• Vascular Malformations
Capillary malformations (slow flow)
Venous malformations (slow flow)
 Lymphatic malformations (slow flow)
 Arteriovenous malformations (fast flow)
Combined malformations (slow and/or fast flow)
History
• Adopting specific terminology has allowed investigators:
better categorize vascular birthmarks
predict their clinical behavior and prognosis
Vascular Tumors
Infantile Hemangiomas
• The most common soft tissue tumor of infancy
• Infants with hemangiomas were more likely to be:
 female
Caucasian
low birth weight
 premature
 products of multiple gestation pregnancies
 born to older mothers
Pathogenesis
• Several hypotheses have been proposed to explain their pathogenesis
• Several mechanisms under the control of multiple genes
Pathogenesis
• Hemangioma Endothelial Cells: Origin, Defects and Signaling
• Placental Hypothesis
• Hypoxia and Other Extrinsic Factors
• Factors Influencing Natural History
Hemangioma Endothelial Cells:
Origin, Defects and Signaling
• Recent evidence suggests:
 hemangiomas may be derived from endothelial progenitor cells or multipotent
stem cells
• During hemangioma formation, vasculogenesis as well as
angiogenesis might occur
Vasculogenesis: de novo formation of vessels from progenitor/stem cells
Angiogenesis: formation of new vessels from existing ones
Hemangioma Endothelial Cells: Origin, Defects
and Signaling
• Familial hemangiomas:
chromosome 5q
• Sporadic hemangiomas
loss of heterozygosity of 5q
• Suggesting that gene(s) at this locus may be involved in
Hemangioma formation
• Increased expression of the endothelial cell-specific Tie-2 tyrosine
kinase
Placental Hypothesis
• Hemangioma cells are either of placental origin (e.g. via embolization)
or undergo differentiation toward a placental microvascular
phenotype
• Glucose transporter protein-1 (GLUT-1) is expressed by:
infantile hemangiomas during all phases of their development (proliferating,
involuting, involuted)
the placenta
 not by other vascular tumors or malformations
Hypoxia and Other Extrinsic Factors
• A role for hypoxia in the pathogenesis of hemangiomas is supported
by:
their association with hypoxic placental changes
prematurity/low birth weight (often caused by placental insufficiency)
• Hypoxia upregulates expression of GLUT-I and VEGF, leading to
mobilization of endothelial progenitor cells
Factors Influencing Natural History
• In the proliferative phase, hemangiomas express:
 markers of proliferation (e.g. proliferating cell nuclear antigen [PCNA])
increased levels of pro-angiogenic molecules such as VEGF and basic fibroblast growth
factor (bFGF)
• Indoleamine 2,3-dioxygenase (IDO):
 inhibits T-cell activation
 is highly expressed by macrophages, dendritic cells, the placenta and proliferating
hemangiomas
increased IDO activity protects proliferating hemangiomas from immune surveillance
downregulation of IDO production may therefore have a role in involution
• Increased expression of angiogenesis inhibitors and apoptosis promoters has
been observed in involuting hemangiomas
Vascular Malformations
Introduction
• Vascular malformations:
localized defects of vascular morphogenesis
caused by dysfunction in pathways regulating the formation of vascular channels
during embryonic development
have a quiescent endothelium
 do not exhibit the markers of endothelial cell proliferation seen in infantile
hemangiomas during their proliferative phase
Introduction
• Because vascular malformations are not truly proliferating lesions
with cellular hyperplasia, the suffix "oma" (meaning "tumor") has
been deemed inaccurate
• The terms "angioma", "lymphangioma" and "hemangioma" should
no longer be used for vascular malformations
Introduction
• Vascular malformations are subcategorized depending on:
 the predominant anomalous channels
flow characteristics: slow-flow or fast-flow
• A slow-flow vascular malformation may be:
 capillary (CM)
 venous (VM)
lymphatic (LM)
Introduction
• A fast-flow vascular malformation combines arterial anomalies and
arteriovenous shunting, creating the nidus of an arteriovenous
malformation (AVM)
• Complex-combined vascular malformations are designated as:
capillary-venous (CVM)
capillary-lymphatic (CLM)
capillary-lymphaticvenous (CLVM)
lymphatic-venous (LVM)
capillary-arteriovenous (C-AVM)
lymphatic-arteriovenous (L-AVM)
Pathogenesis
• Rare familial transmission of vascular malformations has allowed:
 mapping of susceptibility to certain inherited lesions to precise chromosomal
locations
 identification of the associated gene and disease causing mutations
discovery of the function of the encoded proteins
 clarification of the role the dysfunction plays in regulatory pathways
Pathogenesis
• It remains to be determined if sporadic vascular malformations, which are
far more frequent than familial ones, are caused by the same gene
mutations
• Some data support this hypothesis
• Cutaneous and mucosal venous malformations (VMCM)
AD; sporadic (with somatic mutations in lesional tissue)
• Such research brings hope of gene therapy or currently unimaginable novel
treatment strategies
THE END